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Current Topics in Medicinal Chemistry, 2022, 22, 891-920

CURRENT FRONTIER
ISSN: 1568-0266
eISSN: 1873-4294

Vascular Endothelial Growth Factor Receptors [VEGFR] as Target in

Breast Cancer Treatment: Current Status in Preclinical and Clinical
Impact
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Mohammad Malekan1 and Mohammad Ali Ebrahimzadeh2,*

Current Topics in Medicinal Chemistry

1
Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; 2Department
of Medicinal Chemistry, Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of
Medical Sciences, Sari, Iran
Abstract: Breast cancer [BC] is one of the most common cancers among women, one of the leading
causes of a considerable number of cancer-related death globally. Among all procedures leading to
the formation of breast tumors, angiogenesis has an important role in cancer progression and out-
ARTICLE HISTORY comes. Therefore, various anti-angiogenic strategies have been developed so far to enhance treat-
ment's efficacy in different types of BC. Vascular endothelial growth factors [VEGFs] and their re-
Received: August 19, 2021 ceptors are regarded as the most well-known regulators of neovascularization. VEGF binding to vas-
Revised: January 11, 2022
Accepted: January 20, 2022 cular endothelial growth factor receptors [VEGFRs] provides cell proliferation and vascular tissue
formation by the subsequent tyrosine kinase pathway. VEGF/VEGFR axis displays an attractive tar-
DOI:
10.2174/1568026622666220308161710 get for anti-angiogenesis and anti-cancer drug design. This review aims to describe the existing litera-
ture regarding VEGFR inhibitors, focusing on BC treatment reported in the last two decades.

Keywords: Breast cancer, Angiogenesis, VEGFR inhibitors, Targeted therapy, Clinical trials, Preclinical studies

1. INTRODUCTION endothelial growth factor [VEGF] acts as the main inducers

Breast cancer [BC] is one of the most common cancers
among women that about 24% of new cases have been at-
tributed to it. Indeed, it is the cause of a notable number of
cancer-related death globally [1, 2]. BC has become a major
health issue all over the world. Based on the predictions, BC
incidence could increase to more than 46% by 2040 [3],
which is influenced by various factors including genetic
factors, environmental factors, and lifestyle [4]. The breast
in both men and women mainly comprises fatty tissue that is
known as adipose tissue [5]. In females, breasts usually have
more glandular tissue and network lobes and lobules than
males. In addition, there are lactiferous ducts [also known as
milk ducts] that connect these lobes and lobules [6, 7].
Based on the histological classification of breast malignan-
cies, they are divided into non-invasive and invasive groups.
Non-invasive malignancies include ductal and lobular carci-
noma, while tubular, ductal lobular, invasive lobular, infil-
trating ductal, mucinous, medullary, and infiltrating ductal
carcinomas are classified as the invasive group [8].
The biology and pathology of BC and its progression
have been studied extensively [9]. Angiogenesis is a key
factor in BC progression since it is essential for the tumor's
sufficient oxygen and nutrition supplies [10, 11]. Vascular
*Address correspondence to this author at the Department of Medicinal
Chemistry, Pharmaceutical Sciences Research Center, School of Pharmacy,
Mazandaran University of Medical Sciences, Sari, Iran; Tel: +989111541214;
E-mails: zadeh20@gmail.com; MA.Ebrahimzadeh@mazum.ac.ir
of progressive angiogenesis in tumors, which acts via bind-
ing to vascular endothelial growth factor receptors [VEG-
FRs] [12]. Due to the importance of VEGF, VEGFR, and
their connection in BC physiopathology, considerable ef-
forts have been made aiming to produce natural or synthetic
VEGFR small molecule inhibitors to strongly antagonized
this pathway to slow down tumor progression [13]. A num-
ber of selective and pan-VEGFR inhibitors have been de-
signed so far [14, 15]. Some of them have gained food and
drug administration [FDA] approval after extensive preclin-
ical and clinical investigation and are currently widely used
for treating BC patients [16, 17].
Although surgery and chemotherapy are considered two
primary therapeutic approaches of BC, the above-mentioned
adjuvant drugs have been employed recently and represent-
ed promising results [18, 19]. This new medical treatment
strategy has some advantages. For instance, a lack of drug-
resistant cases and more significant toxicity for each target
have been reported for some agents [20]. This review main-
ly represents a summary of small-molecule VEGFR inhibi-
tors in preclinical studies and clinical trials, with a particular
focus on BC.
2. VEGFS AND VEGFRS IN ANGIOGENESIS: BIOL-
OGY AND CANCER PATHOLOGY
VEGFs are characterized as multifunctional peptides that
could induce angiogenesis and receptor-mediated endotheli-

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892 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
al cell proliferation in vivo and in vitro [21]. VEGFs are
classified into five isoforms, including VEGF-A, VEGF-B,
VEGF-C, VEGF-D, VEGF-E, and placenta growth factor
[PlGF]. Among this family, VEGF-A is considered the most
important factor and is commonly called VEGF [22, 23]. In
normal tissues, angiogenic and anti-angiogenic inducers are
kept in balance; however, cancerous tissues disturb this bal-
ance while tumors expand. VEGFs are triggered with the
activation of endothelial cells to stimulate angiogenesis that
subsequently leads to an increased delivery of oxygen sup-
plies and cells nutrients to malignant cells for survival and
growth [19, 24]. Moreover, these factors can serve as chem-
oattractants for bone marrow-derived stem cells, contrib-
uting to tumor progression after migrating to neoplastic tis-
sues [25, 26].
VEGFs primarily bind to three structurally similar recep-
tors, including VEGFR-1 [FLT1], VEGFR-2 [KDR], and
VEGFR-3 [FLT4]. The VEGFRs are a receptor family with
intracellular tyrosine kinases activity, which lead to the ini-
tiation of signaling pathways that mediate angiogenesis pro-
cesses [27, 28]. The main events which occur immediately
after VEGFs binding to these receptors are receptor dimeri-
zation, kinase activation, and autophosphorylation. [29, 30].
VEGF-A functions via two membrane-associated receptors,
VEGFR-1 and VEGFR-2. In contrast, VEGF-C and VEGF-
D identify VEGFR-3 and VEGFR-2. VEGFR-1 is the only
known receptor for VEGF-B and PIGF [31-33] (Fig. 1).
2.1. VEGFR-1
VEGFR-1 is a typical tyrosine kinase receptor with sev-
en immunoglobulins [Ig]-like domains in the extracellular
region and an intracellular region containing a tyrosine ki-
nase domain. It mainly acts in the initial steps of inflamma-
tion formation and is chiefly expressed by vascular endothe-
lial cells [34, 35]. The tyrosine kinase activity of VEGFR-1
is more limited than VEGFR-2, although VEGF-A attaches
to VEGFR-1 with a higher affinity than VEGFR-2 [36, 37].
It is determined that the juxtamembrane region of VEGFR-1
via replacing with VEGFR-2 paralogous region led to more
potent downstream signals [38]. Also, it is shown that ex-
pressing both VEGFR-1 and VEGFR-2 in the cell lines sig-
nificantly enhanced phospholipase Cγ [PLCγ] signaling
pathway activation compared to expression of VEGFR-1
alone [39]. Moreover, VEGFR-1 has the potential of hetero-
dimerization with VEGFR-2. VEGFR-1 and VEGFR-2 het-
erodimerization might be stimulated by other ligand dimers
like VEGF/PGF, which may increase VEGF-mediated neo-
vascularization [40].
VEGFR-1 effects and expression have been investigated
in different tumors. Jackson et al. showed VEGFR-1 ex-
pression increased in well-differentiated neoplastic prostate
cells whereas decreased in poorly differentiated tumor cells
[41]. Frank et al. revealed that VEGFR-1 plays a vital role
in melanoma tumor growth by adjusting laminin formation
and vasculogenic mimicry in malignant melanoma-initiating
cells [42]. Also, similar results with mentioned studies were
reported for other cancers including, pancreatic cancer [43],
colorectal cancer [44, 45], multiple myeloma [46], and BC
[47, 48].
Malekan and Ebrahimzadeh
2.2. VEGFR-2
VEGFR-2 is almost exclusively placed on endothelial
cells. It is the major receptor in tumor angiogenesis devel-
opment because it regulates endothelial cell migration,
growth, differentiation, cell survival, vessel dilation, and
permeability. Studies revealed that VEGFR-2 activity is
mediated through phospholipase Cγ [PLCγ] and protein ki-
nase C [PKC] signaling pathways [16, 49] (Fig. 1). It is de-
termined that at least four auto-phosphorylation areas exist
within VEGFR-2 with Tyr1054 and Tyr1059 tyrosine resi-
dues, which are required for a maximum of receptor kinase
activity [27]. Also, Takahashi et al. expressed that Tyr1175
has a crucial role in activating of PLCγ/PKC/MAPK path-
way. This signaling pathway plays a vital role in the prolif-
eration of endothelial cells [50]. Holmqvist et al. reported
that the adaptor protein Shb binds to VEGFR-2 and is re-
quired for VEGF-mediated PI3K activity, leading to cellular
migration and stress fiber formation [51].
Like VEGFR-1, VEGFR-2 showed a significant impact
on the progression of cancerous conditions. Yan et al. con-
ducted a study to analyze the VEGFR-2 expression pattern
in BC cell lines. They observed that VEGFR-2 expression
was associated with higher lymph node metastasis of BC
and significantly worse outcome [52]. It was exhibited
VEGFR-2 phosphorylation level was increased by VEGF-A
in pancreas cancer cells and expressed VEGF-A/VEGFR-2
signaling acts as an important inducer of invasion and mi-
gration in these neoplastic cells [53]. Also, in other types of
malignant tumors like melanoma [54], leukemia [55], and
ovarian cancer [56].
2.3. VEGFR-3
The last member of the VEGFRs family is VEGFR-3. It
is less well known than other VEGFRs, while it is deter-
mined that it has crucial roles in cell migration, protection of
lymphatic endothelial cells from apoptosis, and affecting
vascular development after interaction with VEGFR-2 [31,
57]. VEGFR-3 has the potential of making homodimers or
heterodimers. VEGF-C could induce VEGFR-3/VEGFR-2
heterodimer formation, and these receptor complexes initi-
ate various downstream cellular functions following ligand
binding [58]. It is pointed out VEGFR-3 acts via protein
kinase C-dependent activation of the p42/p44 MAPK signal-
ing cascade for its role in tumor growth, survival, and mi-
gration [59]. Also, several other pathways are influenced by
the VEGFR-3 axis, including PKC, PI3K, and PLCγ [23].
VEGFR-3, like other VEGFR members, is pathological-
ly expressed in different tumors cell lines, including lung
[60], breast [61], cervical [62], prostate [63], and colorectal
[64] cancers.
3. ANGIOGENESIS IN BC PROGRESSION
Since angiogenesis plays a crucial role in basic prerequi-
sites of tumorigenesis, extensive studies were conducted to
reveal more evidence concerning this process in BC pro-
gression [65]. Normal mammary tissues only infrequently
induce neovascularization, whereas 90% of cancerous
VEGFRs as a Target in Breast Cancer
Fig. (1). VEGFs and related VEGFRs, main associated signaling pathways, and final effects. (A higher resolution / colour version of this
figure is available in the electronic copy of the article).
mammary tissues strongly initiate angiogenesis [66]. Sever-
al studies showed that microvascular density [MVD] could
be a prognostic indicator for BC patients [67-70]. Indeed,
high MVD is significantly associated with poor prognosis,
bigger tumor size, higher grades of tumor, and lymph node
metastasis [70-72]. Multiple vascular growth factors engage
in invasive human BC neovascularization, such as basic
fibroblast growth factor [bFGF], transforming growth factor
beta-1 [TGFβ-1], platelet-derived endothelial cell growth
factor [PD-ECGF], PlGF, and VEGFs [73, 74]. Among all
these factors, the VEGF family compromises the most criti-
cal factors. There are many inducers for VEGFs. For in-
stance, cytokines [In particular, IL-8], hormones, hypoxia-
inducible factors [HIFs], loss of functional p53, and human
epidermal growth factor receptor 2 [HER2] overexpression
[75].
It has been observed that the VEGF expression has an
inverse correlation with the overall survival in both node-
positive and node-negative cancer cases [76, 77]. Further-
more, increased VEGF expression has been connected with
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 893
impaired response to chemotherapy in advanced BC patients
[78]. Schmidt et al. tested the expression of VEGFR-1 by
RT-PCR and Western blot in six BC cell lines. They also
examined 93 BC lesions to evaluate the clinical significance
of VEGF and VEGFR-1 expression. They observed
VEGFR-1 mRNA in all six cell lines, and protein expres-
sion was detected in five cell lines. It is concluded that the
expressions of VEGFR-1 and VEGF are not only associated
together but also correlated with node-negative tumor stages
[79]. Similar to these findings also were found by Srabovic
et al. [80]. Moreover, Ning et al. reported that VEGFR-1
was identified in 60.6% of invasive BC tissues, which leads
to the promotion of BC progression and metastasis [81].
Ryden et al. evaluated VEGF-A and VEGFR2/KDR ex-
pression in 102 BC tissues by immunohistochemistry, and
also they analyzed VEGF-A165 with enzyme immunoassay
[ELISA]. They concluded that VEGFR2/KDR expression is
associated with VEGF in BC; indeed, they are co-expressed.
Furthermore, analyzing the levels of VEGF-A165 in the
protein extracts was correlated with poor short-time survival
894 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
[82]. It is determined the expression of VEGFR-2 is posi-
tively associated with lymph node metastasis of BC. Be-
sides, significantly worse overall survival was observed in
the condition of high levels of VEGFR-2 [52].
Valtola et al. expressed that a significant number of
VEGFR-3 positive vessels were detected in invasive BC,
and VEGF-C secretion acts as an angiogenic growth factor
for blood vessels. This signaling network is associated with
angiogenesis, permeabilities of lymphatic and blood vessels,
and metastasis in BC cells [61]. Similarly, it is stated by
Raica et al. [83]. Also, Iterson et al. reported that VEGF-D
is correlated with VEGFR-3, leading to higher metastasis in
human invasive lobular BC cells [84].
4. VEGFR INHIBITORS: FROM HYPOTHESIS TO-
WARD CLINICAL DRUGS, AND MECHANISM OF
ACTION
The first tyrosine kinase inhibitors [TKIs] acts via inhi-
bition of EGFR and other tyrosine kinases, which were low
potent and nonspecific. These inhibitors were known as nat-
ural compounds like quercetin and erbstatin. The first syn-
thesized receptor TKIs, made from the benzene malono-
nitrile group based on natural inhibitors, mimic the struc-
ture, and generally, they were more potent products [85, 86].
Also, other approaches like molecular modeling analysis via
X-ray crystallographic data and screening of large peptide
libraries for discovering compounds with TK inhibitory ac-
tion. Afterward, the combination of these methods has been
led to the identification and designing of several potential
inhibitor molecules [31].
The adenosine triphosphate [ATP]‐binding cleft of ki-
nase domain protein comprises the ribose sugar, adenine
ring, and three phosphate groups. Generally, there is three
class of TKIs. Class I are ATP-competitive kinase inhibi-
tors, and classes II and III are non‐ATP‐competitive. ATP-
competitive inhibitors [class I] act by creating one to three
hydrogen bonds. Classes II and III induce a conformational
shift in the target enzyme and interrupt the related signaling
stream [87]. Small molecule VEGFR inhibitors compete for
ATP binding sites within the tyrosine kinase receptors and
antagonize the highly conserved tyrosine kinase domain.
Consequently, disrupt their phosphorylation and down-
stream signaling [88]. Nowadays, they are assumed as the
most known VEGFRs targeted therapy, and they have at-
tracted much attention from researchers, especially in the
field of oncology as a cancer therapeutic approach.
5. NATURAL PRODUCTS WITH VEGFR ANTAGO-
NISTIC ACTIVITY IN BC TARGET THERAPY
For decades, natural compounds and medicinal herbs
have attracted particular attention for their tumor healing
properties and antitumor activity. It is revealed that these
natural agents are involved in inhibiting carcinogenesis
through multiple pathways like angiogenesis, cell migration,
cell proliferation, survival, and metastasis [89]. VEGFR
antagonistic activity was detected in some agents, including
epigallocatechin gallate [90], resveratrol [91], curcumin
Malekan and Ebrahimzadeh
[92], wogonin [93], triptolide [94], farnesiferol C [95]. Here
we take a look at applying these agents in BC therapy.
5.1. Epigallocatechin Gallate [EGCG]
The major component of green tea, is considered a tumor
progression suppressor. It was determined that this agent
acts through the inhibition of various types of receptor tyro-
sine kinases receptors such as VEGFRs. Shimizu et al. in-
terestingly exhibited that treatment with 25 μg/ml EGCG
within 3 hours decreased expression of HIF-1α protein and
VEGF, and within 6 hours reduced the expression of
VEGFR-2 [90]. Hong et al. applied EGCG in human
MDA-MB-231 BC cells lines. They observed that this agent
has a significant potential for inhibiting tumor cell growth
through the inactivation of the β-catenin axis [96]. Moreo-
ver, it was shown that EGCG could be a sensitizer of cyto-
toxic agents like paclitaxel on breast carcinoma cell lines in
vivo [97]. EGCG also indicated a chemopreventive potential
in MCF-7 BC cell lines. Indeed, EGCG inhibits tumor
growth via in vivo downregulation of miR-25 expression,
which causes apoptosis induction and cell proliferation inhi-
bition [98].
5.2. Resveratrol
A non-flavonoid polyphenol found in some dietary
sources [including berries, grapes, pomegranate, soybeans,
and peanuts], exhibited antiangiogenic properties via a sup-
pressive effect on soluble-VEGFR-1 protein release and
VEGFR-1 promoter activity [91, 99]. Several studies inves-
tigated resveratrol for its anti-tumor activity. Tang et al.
displayed that this agent inhibited migration and invasion of
human BC MDA-MB-435 cells. Indeed, resveratrol acted by
restricting of PI3K/Akt signaling pathway [100]. Also, Gali-
cia et al. showed that resveratrol increased sensitivity to
cisplatin in resistant MCF-7 BC cells through downregulat-
ing Rad51 expression [101]. Zhu et al. carried out a ran-
domized, double-blind, placebo-control trial on 39 women
with increased breast cancer risk to explore the benefits of 5
or 50 mg trans-resveratrol twice daily for 12 weeks. Then,
they monitored the methylation of four cancer-related genes,
including p16, RASSF-1α, APC, CCND2. It was concluded
that RASSF-1α methylation decreased following trans-
resveratrol and resveratrol-glucuronide increase. Also, they
suggested that studies with a larger sample size should vali-
date this novel mechanism [102].
5.3. Curcumin
A biologically active polyphenol compound derived
from turmeric, could present an antiangiogenic impact in
cancer masses via a cascade of cellular regulation which
engages HIF-1α, mTOR, VEGF, and VEGFR [92]. Hu et al.
showed curcumin has anti-metastatic and anti-proliferative
activities in MCF-7 and MDA-MB-231 BC cell lines [103].
Also, induction of radiosensitivity and chemosensitivity for
BC treatment procedures are other crucial characteristics of
curcumin [104, 105]. Investigation of curcumin in a ran-
domized, double-blind, placebo-controlled clinical trial
VEGFRs as a Target in Breast Cancer Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 895

showed some encouraging clinical benefits for curcumin
combined with paclitaxel. Saghatelyan et al. enrolled 150
women with BC to examine the paclitaxel [80 mg/m2] plus
curcumin [300 mg intravenously, once per week]. They
treated their cases for 12 weeks with 3 months of follow-up.
As a result, they expressed that the objective response rate
[ORR] of patients who received curcumin was significantly
better than that of the placebo group [106].
5.4. Wogonin
An O-methylated flavonoid compound derived from
Scutellaria baicalensis, has a notable angiogenesis inhibitory
effect through VEGFRs. Lu and colleagues showed that
wogonin limited the phosphorylation of VEGFR-2 through a
significant drop in VEGF-triggered phosphorylated forms of
p38, ERK, and AKT [93]. Investigating the anti-BC effects
of wogonin in vitro and in vivo revealed that this agent
could be a practical therapeutic and chemopreventive ap-
proach against both ER-positive and -negative BCs [107].
Moreover, Huang et al. examined wogonin for its pro-
apoptotic role in MCF-7 BC cells. This study exhibited
wogonin acts as a pro-apoptotic agent by mediating caspa-
ses, ERK, and PI3K/Akt pathways [108].
5.5. Triptolide
The major compound of Chinese herbal medicine Trip-
terygium wilfordii [also known as Thunder God Vine], has a
potent suppressive function on angiogenesis via downregu-
lation of endothelial receptors like Tie2 and VEGFR-2 ex-
pression [94]. Tang et al. also expressed that this agent
could drive an antiestrogenic role in human BC cell line
[MCF-7] and immature female mice, in vitro and in vivo
[109]. Furthermore, it was shown that triptolide not only
decreased BC cell growth but also induced the death of BC
cells [110].
6. VEGFR INHIBITORS IN BC TARGET THERAPY:
PRECLINICAL AND CLINICAL STUDIES
After several years of investigation and making hypothe-
ses on processes related to angiogenesis and its agents, fi-
nally, this knowledge has reached a point to be practically
applied in various malignancies, including BC therapy, es-
pecially in the past two decades [17, 111]. Extensive pre-
clinical and clinical trial studies were conducted to deter-
mine the efficacy and safety of VEGFR-TKIs in BC target
therapy [112]. In the following sections, the preclinical and
mainly clinical studies of VEGFR-TKIs conducted in BC
treatment are discussed.
6.1. Pan-VEGFR Inhibitors
Many potent VEGFR inhibitors can inhibit VEGFR-1,
VEGFR-2, and VEGFR-3. These molecules are classified as
pan-VEGFR inhibitors. Based on the available evidence on
BC therapy, we will review and highlight the important
findings concerning pazopanib [GW786034], cediranib
[AZD2171], dovitinib [TKI258, CHIR258], nintedanib
[BIBF 1120], axitinib, regorafenib [BAY 73-4506], len-
vatinib [E7080], tivozanib [AV-951], and motesanib [AMG-
706] (Table 1).

Table 1. Pan-VEGFR inhibitors name, targets, structure and formula.

Name Targets IC50 for VEGFR Targeting Structure and Formula Refs.

VEGFR-1, VEGFR-1: 10 nM
VEGFR-2, VEGFR-2: 30 nM
Pazopanib
VEGFR-3, c-Kit, [113]
[GW786034] VEGFR-3: 47 nM
PDGFR, FGFR,
and c-Fms [cell-free assays]
C21H23N7O2S

VEGFR-1/FLT1, VEGFR-1: 5 nM
VEGFR-2/KDR, VEGFR-2: 0.5 nM
Cediranib VEGFR-3/FLT4,
VEGFR-3: ≤3 nM [120]
[AZD2171] c-Kit, PDGFRβ,
FGFR1, and [Human umbilical vein endothe-
PDGFRα lial cells]
C25H27FN4O3

VEGFR-1/FLT1,
VEGFR-2/Flk1, VEGFR-1: 10 nM
Dovitinib VEGFR-3/FLT4, VEGFR-2: 13 nM
[TKI258, FLT3, c-Kit, [126]
CHIR258] FGFR1, FGFR3, VEGFR-3: 8 nM
PDGFRβ, and [cell-free assays]
CSF-1R/c-Fms C21H21FN6O

(Table 1) contd…
896 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 Malekan and Ebrahimzadeh

Name Targets IC50 for VEGFR Targeting Structure and Formula Refs.

VEGFR-1/FLT1,
VEGFR-1: 0.1 nM
VEGFR-2/Flk1,
Axitinib VEGFR-2/KDR, VEGFR-2: 0.2 nM
[138]
[AG 013736] VEGFR3, PDG- VEGFR-3: 0.1-0.3 nM
FRβ, Kit, PDG-
[porcine aorta endothelial cells]
FRα
C22H18N4OS

VEGFR-1: 2 nM
VEGFR-1,
Motesanib VEGFR-2, VEGFR-2: 3 nM
[144]
[AMG-706] VEGFR-3, c-Kit, VEGFR-3: 6 nM
c-Ret, PDGFR
[cell-free assays]

C22H23N5O

VEGFR-1/FLT1,
VEGFR-1: 22 nM
VEGFR-2/KDR,
Lenvatinib VEGFR-3/FLT4, VEGFR-2: 4 nM
[155]
[E7080] RET, PDGFRβ, VEGFR-3: 5.2 nM
FGFR1, PDG-
[cell-free assays]
FRα, Kit
C21H19ClN4O4
VEGFR-1,
VEGFR-2,
VEGFR-1: 30 nM
VEGFR-3,
Tivozanib [AV- EphB2, PDG- VEGFR-2: 6.5 nM
[149]
951] FRα, PDGFRβ, VEGFR-3: 15 nM
c-Kit, Tie-2,
[cell-free assays]
EphB4, FGFR1,
c-Met, Abl C22H19ClN4O5

VEGFR-1,
VEGFR-2,
VEGFR-1: 34 nM
VEGFR-3, LCK,
Nintedanib [BIBF FLT3, FGFR2, VEGFR-2: 13 nM
[156]
1120] PDGFRα, PDG- VEGFR-3: 13 nM
FRβ, FGFR1,
[cell-free assays]
FGFR3, Src,
Lyn, and FGFR4
C31H33N5O4

VEGFR-1,
VEGFR-1: 13 nM
VEGFR-2,
Regorafenib VEGFR-3, RET, VEGFR-2: 4.2 nM
[154]
[BAY 73-4506] Raf-1, Kit, B-Raf VEGFR-3: 46 nM
[V600E], PDG-
[cell-free assays]
FRβ, B-Raf

C21H15ClF4N4O3

6.1.1. Pazopanib [GW786034] determine the anti-tumor and inhibitory effect of this mole-
cule [114, 115]. Hosaka et al. showed that pazopanib sup-
For the first time, Harris et al. discovered pazopanib as a
presses synovial sarcoma cell proliferation and via blocking
novel and potent VEGFR-1, 2, and 3 inhibitors with the
the PI3K-AKT pathway. Also, they concluded that based on
half-maximal inhibitory concentration [IC50] of 10, 30, and
the results of their tumor xenograft model experiments, paz-
47 nM in cell-free assays, respectively [113]. After that,
opanib has the potential to be investigated as a possible
more in vitro and in vivo studies have been conducted to
VEGFRs as a Target in Breast Cancer
agent in synovial sarcoma treatment clinically [114]. Pazo-
panib has been used for BC targeted therapy in several clin-
ical trials as well.
Taylor et al., in a phase II trial, used pazopanib for 20
metastatic BC patients [median age of 56 years] who were
treated with up to two prior lines of chemotherapy. These
patients received 800 mg daily of pazopanib until progres-
sion. They concluded that pazopanib provided disease sta-
bility in BC patients with the median time to progression of
about 5.3 months, although using this agent did not meet the
efficacy criteria. Also, they reported that pazopanib did not
generate significant severe toxicity and no treatment-related
deaths. However, a low incidence of grade 3 and 4 side-
effects was observed, including transaminitis, hypertension,
and neutropenia in three patients and gastrointestinal hemor-
rhage in one patient. As limitation, they expressed that this
study is not powerful enough to show significant conclu-
sions and suggested that prospective phase III studies should
validate pazopanib clinical results [116]. Johnston et al.
conducted a phase II randomized multicenter study and in-
vestigated the addition of pazopanib to lapatinib [cohort 1:
lapatinib 1,000 mg + pazopanib 400 mg OR lapatinib 1,500
mg monotherapy]; cohort 2: lapatinib 1,500 mg + pazopanib
800 mg] in patients with HER2-positive advanced BC as
first-line therapy. The study enrolled 190 patients. Cohort 1
included 69 patients for lapatinib + pazopanib [median age
of 50 years old] and 72 patients for lapatinib monotherapy
[median age of 54 years old], and cohort 2 included 36 pa-
tients [median age of 54 years old]. They found out that the
addition of pazopanib to lapatinib did not improve progres-
sive disease rate [PDR] and increased the toxicity compared
with lapatinib monotherapy, particularly in side effects like
diarrhea and liver enzyme abnormalities. However, this
combination increased the response rate [RR] [117].
Another study with the relatively same method and the
topic was carried out by Cristofanilli et al. [118]. They
reached the same result as the prior trial. They reported that
combining these two drugs enhanced the RR and increased
the toxicity but represented no improvement in progression-
free survival [PFS]. Also, they declared that both lapatinib
and pazopanib were correlated with cardiac dysfunction,
especially for patients who priorly received anthracycline
chemotherapy [118]. In 2015, Tan et al. [119] evaluated
paclitaxel in combination with pazopanib following doxoru-
bicin and cyclophosphamide as neoadjuvant therapy for
HER2-negative locally invasive BC patients. Their primary
end-point was a pathologic complete response [pCR]. They
enrolled 101 women [median age of 51 years old] in stage
III HER2-negative breast cancer. Patients received four cy-
cles of doxorubicin 60 mg/m2 and cyclophosphamide 600
mg/m2 every three weeks followed by paclitaxel 80 mg/m2
weekly for four cycles concurrently with pazopanib 800 mg
orally daily prior to surgery. After surgery, pazopanib was
received daily for 6 months. They concluded that the addi-
tion of pazopanib to a paclitaxel regimen produced toxicity
and did not show obvious benefit over what has been seen
with chemotherapy alone [119].
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 897
6.1.2. Cediranib [AZD2171]
Cediranib is a highly potent pan-VEGFR inhibitor, espe-
cially for VEGFR2/KDR. Its IC50 for VEGFR-1, 2, and 3 is
5, 0.5, and ≤3 nM, respectively [120, 121]. Further studies
like the study conducted by Morton et al. tested the anti-
tumor activity of cediranib preclinically. They tested cedi-
ranib in vivo against sarcomas, glioblastoma, and neuroblas-
toma in childhood tumor xenograft models alone or com-
bined with standard cytotoxic agents like cyclophospha-
mide, vincristine, cisplatin, and rapamycin. They concluded
that the addition of cediranib to cytotoxic chemotherapy
agents did not show a significant positive effect compared to
chemotherapy alone, even in one case decreased benefits of
treatment [122]. In addition, cediranib has been investigated
in several trials of BC targeted therapy.
In an open-label, phase I dose-escalation trial with twen-
ty ovarian cancer and eight triple-negative breast cancer
[TNBC] patients, Liu et al. investigated the efficacy of
cediranib plus olaparib. Cediranib was utilized as 10 and 15
mg tablets and olaparib 50 mg capsules. They started with
the dose of cediranib 20 mg daily and olaparib 100 mg twice
daily. Although dose-limiting toxicities and maximum toler-
ated dose were their primary objectives, they assumed clini-
cal activity by clinical benefit rate [CBR] and PFS. They
concluded that the combination of these two medications
was a tolerable regimen. Clinical responses were observed
in 44% of ovarian cancer patients. However, none of the
seven BC patients with evaluable status [from eight pa-
tients] achieved clinical responses. Hypertension, fatigue,
neutropenia, and thrombocytopenia were some reported
adverse events [123].
Another phase I dose-escalation trial was conducted to
evaluate bevacizumab and cediranib in patients with ad-
vanced solid tumors. They had three BC patients. Bevaci-
zumab was administrated intravenously on days 1 and 15
combined with cediranib orally on days 1 to 21 per cycle.
Bevacizumab started with dose of 3 mg/kg and increased to
5 mg/kg and 10 mg/kg. Cediranib 15 mg was administrated
as the first dose, and 20 mg, 30 mg, and 45 mg were the
following doses. They generally reported central nervous
system bleeding and severe hypertension as side effects for
cediranib and bevacizumab at a dose of 20 mg/day and 5
mg/kg every two weeks, respectively. Also, they noted as a
limitation that the pharmacokinetic drug-drug interaction of
these two agents could not be analyzed. Furthermore, it was
recommended that more studies should investigate the effi-
cacy of this combination in cancer patients [124].
Hyams et al. studied cediranib plus fulvestrant on hor-
mone-sensitive metastatic BC patients in a randomized-
controlled phase II trial. They divided patients into two
groups. The first group included 31 patients who received
cediranib plus fulvestrant and the second group had 31 pa-
tients who received placebo plus fulvestrant. Cediranib was
received at the dose of 45 mg/day orally and fulvestrant LD
intramuscularly 500 mg on day 1, 250 mg on days 15 and
29, and every 28 days thereafter. They concluded that
898 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
combining these two drugs could have clinical activity
through improving PFS and objective response rate [ORR]
in patients, but it is not statistically significant. Also,
cediranib [45 mg/day] was not sufficiently well tolerated.
Diarrhea [68 %], fatigue [61 %], and hypertension [55 %]
were the most common side effects in the cediranib arm.
Interestingly, they suggested that a lower dose of 30 mg
cediranib could be a good choice for future trials in their
study setting [125].
6.1.3. Dovitinib [TKI258, CHIR258]
Dovitinib is a multitargeted receptor tyrosine kinase
[RTK] inhibitor that can suppress VEGFR-1, VEGFR-2,
and VEGFR-3 with IC50 of 10, 13, and 8 nM in cell-free
assays, respectively [126]. Several preclinical studies were
conducted to determine this molecule's anti-tumor activity in
different cancer types such as colon cancer and hepatocellu-
lar carcinoma [127, 128]. Huynh et al. used 21-0208 and
SK-HEP1 cell lines and patient-derived models to determine
dovitinib's antitumor, antiangiogenesis, and antimetastatic
activities preclinically in hepatocellular carcinoma. They
monitored changes in FGFR, VEGFR, and platelet-derived
growth factor receptor [PDGFR] biomarkers and also ana-
lyzed microvessel density, apoptosis, and cell proliferation.
They expressed that dovitinib exhibited significant anti-
tumor and antimetastatic activities in hepatocellular carci-
noma xenograft models [128]. After that, this molecule was
used in clinical trial studies and BC was one of the treatment
targets for this drug.
André et al. investigated dovitinib with a focus on its fi-
broblast growth factor receptor [FGFR] inhibitory effect in
BC patients. They not only studied dovitinib in their trial but
also evaluated the effect of dovitinib in BC cell lines and the
FGFR1-amplified xenograft model as a preclinical study.
Their preclinical results displayed monotherapy by dovitinib
has the potential to inhibit proliferation in FGFR1- and
FGFR2-amplified, but not FGFR-normal, and suppress tu-
mor growth in FGFR1-amplified BC xenografts. Clinically,
dovitinib was administered orally at 500 mg/day [5 days
on/2 days off] in 28-day cycles. In 81 HER2-negative meta-
static patients, the unconfirmed response was observed in
five cases, and stable disease was seen in one patient for
more than six months. They generally concluded that dovit-
inib could demonstrate relatively low anti-tumor activity in
patients with BC. In this study, side effects were reported
regardless of the relationship to dovitinib. They observed
that all the BC patients experienced one adverse effect dur-
ing the study, and vomiting [77.8%], diarrhea [76.5%], as-
thenia [67.9%], and nausea [67.9%] were the most common
[129].
Musolino et al. in a randomized, double-blind, placebo-
controlled phase II trial, tried to determine whether the addi-
tion of dovitinib to fulvestrant would enhance outcomes in
HR-positive, HER2-negative advanced BC cases. In this
study, 97 patients from 36 centers were enrolled, and all
patients received 500 mg of fulvestrant and 500 mg of do-
vitinib or placebo orally following a weekly [five days on
and two days off] schedule until patient's expiration, loss to
Malekan and Ebrahimzadeh
follow-up, disease progression, or consent withdrawal. They
concluded that dovitinib, in addition to fulvestrant, showed
promising clinical activity. However, they expressed that the
data in this study should be interpreted with caution because
fewer PFS was seen in patients than was expected. Side ef-
fects were reported regardless of cause, and in dovitinib arm
versus [vs.] placebo arm, the most common ones were diar-
rhea [78.7% vs. 32.0%], nausea [72.3% vs. 22.0%], vomit-
ing [57.4% vs. 8%], asthenia [38.8% vs. 22.0%], headache
[36.2% vs. 6%], and fatigue [34% vs. 26.0%] [130].
6.1.4. Nintedanib [BIBF1120]
Nintedanib is a potent triple angiokinase inhibitor of
VEGFR-1, VEGFR-2, and VEGFR-3 with IC50 of 34, 13,
and 13 nM in cell-free assays, respectively [131]. Preclinical
studies showed that nintedanib has the potential of anti-
tumor activity in various cancer, including BC. Liu et al.,
Hilberg et al. and Reguera-Nuñez et al. investigated
nintedanib effect on TNBC cells lines. They concluded that
this molecule induces tumor apoptosis and shrinkage, inhib-
its tumor cell growth, and generally expressed that
nintedanib may be potentially effective in treating BC cell
lines [132-134].
Moreover, nintedanib has been studied clinically for BC
patients. In the phase I dose-escalation trial, Quintela-
Fandino et al. used nintedanib plus paclitaxel in nine early
HER2-negative BC patients [median age of 48 years old].
The primary objectives were finding recommended phase II
dose and safety and tolerability through dose-limiting toxici-
ties evaluation of this combination followed by adriamycin
plus cyclophosphamide [four cycles]. Doses of paclitaxel
[80 mg m2], adriamycin [60 mg m2], and cyclophosphamide
[600 mg m2] were not escalated and were fixed at standard
doses. They prescribed two levels of nintedanib, level 1: 150
mg twice a day and level 2: 200 mg twice a day. They con-
cluded that nintedanib 150 mg twice a day is recommended
phase II dose, and efficacy at this dose was reported very
promising because pCR was 50% in eight evaluable BC
cases. One grade 3 of neutropenia and two grade 3 lympho-
penias were observed in the 24 cycles administered in level
1 [135]. Moreover, Quintela-Fandino et al. did a phase 0/I
clinical trial in an adjuvant setting to understand pharmaco-
dynamics, pharmacokinetics, and safety of the combination
of nintedanib plus letrozole in 19 enrolled patients BC pa-
tients [median age of 50.6 years old]. Letrozole was fixed at
an oral dose of 2.5 mg/day, and nintedanib was employed at
the dose of 150 mg/twice a day [level 1], 200 mg/twice a
day [level 2], and 250 mg/twice a day [level 3]. Cycle 1 out
of 6 was mandatory for patients and a dose-limiting toxicity
assessment. As a result, they stated that nintedanib [200
mg/bid] combined with letrozole [2.5 mg/d] effectively sup-
pressed both FGFR1 and aromatase in BC patients. Also,
drug-drug interaction caused a moderate rate of tolerability
issues in the long term [136].
Quintela-Fandino et al. also conducted an open-label,
multicenter, phase II, randomized trial to compare efficacy
and toxicity of using 18F-fluoromisonidazole-positron emis-
sion tomography [18F-FMISO-PET] followed by nintedanib
VEGFRs as a Target in Breast Cancer
plus weekly paclitaxel as arm A with 18F-FMISO-PET fol-
lowed by weekly paclitaxel as arm B. They enrolled 128
HER2-negative BC patients, 64 cases in arm A [median age
of 47.2 years old], and 64 cases in arm B [median age of
48.2 years old]. The results suggest that adding nintedanib
to paclitaxel did not benefit HER2-negative patients. Add-
ing nintedanib to paclitaxel showed only some efficacy im-
provement in hormone receptor [HR]-positive patients.
Generally, toxicity in grades 3 and 4 was quite low in both
arms [137].
6.1.5. Axitinib [AG013736]
Axitinib is a potent multi-target inhibitor of VEGFR-1,
VEGFR-2, and VEGFR-3 with IC50 of 0.1 nM, 0.2 nM,
0.1-0.3 nM in porcine aorta endothelial cells, respectively
[138]. The anti-cancer effect of this molecule is extensively
studied in preclinical research. It is determined that axitinib
can be utilized in various cancers such as medullary and
papillary thyroid cancer, human neuroblastoma, and BC
[139-141]. Rossler and colleagues conducted a study to ex-
plore the preclinical activity of axitinib against neuroblas-
toma. They used the GR-N91 cell lines and xenografts were
derived from the bone marrow of an 8-year-old boy with
chemotherapy-pretreated neuroblastoma. They observed that
axitinib decreased the VEGFR-2 phosphorylation and sub-
sequently caused a reduction in microvessel density and
tumor vessels. Hence they concluded that axitinib has an
antitumor activity through its potent antiangiogenic effects
[141].
Moreover, Ma et al. investigated, in vitro and in vivo,
dopamine enhancement effect on axitinib efficacy on MCF-
7/ADR BC cell lines. Furthermore, a pharmacokinetic-
pharmacodynamic model was conducted to determine the
interaction between axitinib and dopamine. The results
showed a significant synergic dopamine effect on axitinib
on tumor growth via a drop in the population of BC's stem-
like cells. The pharmacokinetic-pharmacodynamic model
quantitatively confirmed these results and helped optimize
axitinib and dopamine dosage with efficacy and compliance
consideration in the experiment setting [axitinib 60 mg-
gavage-twice a day; dopamine 50mg/kg-intraperitoneal in-
jection-every three days] [142]. Even though several studies
approved its anti-tumor activity of axitinib, few clinical tri-
als have been conducted on BC patients.
Rugo et al. completed a randomized, placebo-controlled,
double-blind, phase I/II, multicenter study of axitinib plus
docetaxel versus docetaxel plus placebo in 168 patients with
metastatic BC. The Axitinib group included 112 patients
with a median age of 55 years old, and the placebo group
included 56 patients with a median age of 56 years old. Cas-
es received docetaxel 80 mg/m2 once every three weeks
plus axitinib 5 mg twice per day or placebo. They concluded
that time to progression [TTP] did not significantly change
by this combination, but the ORR in the axitinib plus docet-
axel arm was significantly greater than the docetaxel plus
placebo. In point of side effects, this potent oral VEGFR
inhibitor potentially increased grade 3 fatigue and diarrhea,
grades 1 to 2 hypertension, and all grades of stomatitis as
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 899
the most common adverse events. As a limitation, they de-
clared that they enrolled patients without a history of prior
chemotherapy in their study. Hence, they suggested that if
the study enrolled subjects with prior chemotherapy, it
might improve the detecting therapy benefits [143].
6.1.6. Motesanib [AMG-706]
Motesanib is a receptor tyrosine kinase inhibitor with
IC50 values 2, 3, 6 nM for VEGFR 1 to 3, respectively
[144]. Preclinical studies showed that it has anti-tumor ac-
tivity against different cancerous cells such as human non-
small cell lung cancer xenograft models and colorectal can-
cer cells [145, 146]. Furthermore, motesanib is clinically
accessed in human cancers such as BC.
De-Boer et al. conducted a phase I trial to find the
motesanib dosage combined with docetaxel or paclitaxel in
46 metastatic BC patients, as well as evaluation of pharma-
cokinetics, tolerability, and safety. The primary and second-
ary endpoints were dose-limiting toxicities and incidence of
adverse events, respectively. They divided the patients into
five group, cohort A1 [Motesanib 50 mg-one daily +
paclitaxel 90 mg/m2], cohort A2 [Motesanib 125 mg-once
daily+ paclitaxel 90 mg/m2], cohort B1 [Motesanib 50 mg-
one daily + docetaxel 100 mg/m2], cohort B2 [Motesanib
125 mg-once daily + docetaxel 100 mg/m2], and cohort B3
[Motesanib 125 mg-once daily + docetaxel 75 mg/m2].
They observed that motesanib's addition to taxane-based
chemotherapies [paclitaxel or docetaxel] was tolerable up to
the 125-mg orally once-daily dose of that. Also, the ob-
tained ORR of 56% suggests a treatment potential of
motesanib in this setting. In terms of side effects, 40 patients
out of 46 [89%] were observed grade ≥1 motesanib-related
adverse event, and 19 [42%] patients had grade 3
motesanib-related adverse events. Of note, fatigue and diar-
rhea were the most common ones [147]. Moreover, Martin
et al., in phase II, randomized, double-blind, placebo-
controlled trial, tried to determine whether motesanib plus
paclitaxel is more beneficial than placebo plus paclitaxel in
patients with HER2-negative metastatic or locally recurrent
BC. They enrolled 282 cases and divided them into three
groups, the motesanib group [125 mg orally once per day;
N: 91 cases], placebo group [125 mg orally once per day; N:
94 cases], bevacizumab group [125 mg orally once per day;
N: 97 cases]. All the patients received paclitaxel 90 mg/m²
intravenously over 1h every week for 3 weeks before either
motesanib or placebo or bevacizumab. They found that
motesanib has anti-tumor activity in patients but was associ-
ated with frequent severe adverse events at the tested dose
and schedule [148].
6.1.7. Tivozanib [AV-951]
Tivozanib is a potent and selective VEGFR inhibitor for
VEGFR-1, VEGFR-2, and VEGFR-3 with IC50 of 30 nM,
6.5 nM, and 15 nM in cell-free assays, respectively [149].
Taguchi et al. and Nakamura et al. preclinically determined
that tivozanib has anti-tumor activity and affects functional
vascular properties [149, 150].
900 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
Also, tivozanib was examined in phase I dose-escalation
trial with weekly paclitaxel in metastatic BC. The final end-
points were the examination of the safety, tolerability,
pharmacokinetics, and activity of tivozanib in the study set-
ting. Eighteen cases [median age of 48 years old] with no
prior VEGFR tyrosine kinase inhibitor treatment were re-
cruited to receive oral tivozanib [3 weeks on, 1 week off]
plus weekly paclitaxel 90 mg/m2. Tivozanib doses adjusted
into 0.5 mg/day [Cohort 1], 1.0 mg/day [Cohort 2], and 1.5
mg/day [Cohort 3]. It is concluded that tivozanib in combi-
nation with paclitaxel, had encouraging activity in the BC
patients and was acceptable at all dose levels. The maxi-
mum tolerated dose was reported as 1.5 mg/day of tivozanib
and paclitaxel 90 mg/m2 weekly. Moreover, these agents
were well-tolerated. Fatigue, diarrhea, nausea, and neuropa-
thy were the most common side effects [151].
6.1.8. Other Pan-VEGFR Inhibitors
Some pan-VEGFR inhibitors have not been examined in
clinical trials on BC patients yet; however, they were pre-
clinically approved to have the anti-tumor activity against
BC cell lines [152, 153]. Regorafenib [BAY 73-4506] and
lenvatinib [E7080] are included in this group [154, 155].
Regorafenib is a multi-target inhibitor for VEGFR-1,
VEGFR-2, and VEGFR-3 with IC50 of 13 nM, 4.2 nM, and
46 nM in cell-free assays, respectively [156]. Mehta et al.
examined the radiosensitizing effects of regorafenib on
TNBC MDA-MB-231 and SUM159PT human cell lines. It
is revealed that regorafenib decreased cell proliferation and
enhanced the radiosensitivity of these cell lines [152].
Lenvatinib is also a potent multi-target inhibitor, mostly
for VEGFR-2 and VEGFR-3 with IC50 of 4.0 nM and 5.2
nM and a less potent inhibitor against VEGFR-1 with IC50
of 22 nM in cell-free assays [155]. Matsui et al. conducted a
study to determine the effect of lenvatinib in lymphangio-
genesis and lymph node metastases of human mammary
breast tumors in MDA-MB-231 cell lines. As a result, it has
been shown that inhibition of VEGFR-2 and VEGFR-3 have
a promising potential as a new strategy to suppress localized
lymph node and distant lung metastases [153].
6.2. Selective-VEGFR Inhibitors
Some molecules are selective-VEGFR inhibitors, which
means they can suppress one or two of VEGFR[s]. Based on
available preclinical and clinical evidence that investigated
these inhibitors on BC, we discuss sunitinib [SU11248],
sorafenib [BAY 43-9006], vandetanib [ZD6474], apatinib
[YN968D1], cabozantinib [XL184, BMS-907351], PD173074,
semaxanib [SU5416], ponatinib [AP24534], foretinib
[GSK1363089], brivanib [BMS-582664], and ENMD-2076
(Table 2) in the following sections.
6.2.1. Sunitinib [SU11248]
Sunitinib is a selective inhibitor for VEGFR-2 with IC50
of 80 nM in cell-free assays [88, 157]. Several studies re-
vealed that sunitinib could use as a therapeutic agent for
tumor cell models. Abrams et al. conducted a study on the
MDA-MB-435-derived BC cell lines and concluded that this
Malekan and Ebrahimzadeh
agent, combined with BC standard care, markedly enhanced
anti-cancer effects, and also they declared that sunitinib has
the potential to be applied in BC clinical treatment [158].
Furthermore, it is revealed that sunitinib in other types of
tumor such as leukemic cells has positive anti-cancer effects
[159-162]. Following these findings, extensive clinical trials
are conducted to test sunitinib on BC patients clinically.
Mayer et al. investigated sunitinib in phase II random-
ized open-label multicenter trial as a first-line treatment for
46 metastatic BC patients. They compared sunitinib's impact
on patients into two groups, paclitaxel plus bevacizumab
plus sunitinib versus paclitaxel plus bevacizumab. They
carried out the study in three-phase based on sunitinib dos-
es. They increased the sunitinib dose from 25 mg/day to
37.5 mg/day, and in each phase, they evaluated the safety to
permit the patients to follow the phases. They reported that
combining sunitinib with bevacizumab plus paclitaxel in
standard doses is not feasible and suggested that further
studies are required in this field to reach a firm conclusion.
In terms of side effects, they reported that adding sunitinib
caused an increase in toxicity in patients, mainly grade 3
and 4 hematological adverse events like leukopenia, neutro-
penia, and febrile neutropenia. As well as gastrointestinal-
related adverse events, including nausea, diarrhea were
common [163]. Another multicenter phase II randomized
trial evaluated sunitinib as consolidation therapy between 3
and 5 weeks after taxane-based chemotherapy in 56 women
with HER2-negative metastatic BC. They divided patients
into two arms, arm A received sunitinib [N: 36, median age:
58 years old] and arm B with no therapy was the control [N:
19, median age: 59 years old]. Patients in arm A received 50
mg sunitinib for 4 weeks followed by a drug-free interval of
2 weeks, also 6-week cycles of sunitinib 37.5 mg until dis-
ease progression. They declared that the study's main hy-
pothesis, sunitinib benefits as consolidation therapy after
taxane chemotherapy, was not confirmed, and the toxicity
was notable. The primary end-point of PFS ≥5 months was
obtained in 10 of 36 patients [median PFS, 2.8 months] with
sunitinib therapy in 4 of 19 patients [median PFS, 3.1
months] without sunitinib [164].
Moreover, Cardoso et al. explored sunitinib as first-line
therapy combined with docetaxel and trastuzumab. They
enrolled 26 patients with HER2-positive metastatic BC. Of
these patients, 24 cases received at least one dose of
sunitinib plus docetaxel and trastuzumab, but one patient did
not receive sunitinib. Finally, 23 out of 25 treated patients
discontinued due to disease progression. They concluded
that this method has a preliminary anti-tumor action for
metastatic HER2-positive BC patients as a first-line treat-
ment. In addition, an acceptable toxicity profile was ob-
served [165].
Bergh et al. conducted a prospective and randomized
phase III study to test sunitinib in combination with docet-
axel versus docetaxel alone. In this study, 593 patients en-
rolled from 127 sites in 27 countries were randomly selected
to receive either sunitinib plus docetaxel [n=296] or docet-
axel alone [n= 297]. They achieved that the sunitinib-doce-
taxel regimen improved ORR but did not increase either
VEGFRs as a Target in Breast Cancer Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 901

Table 2. Selective VEgfr inhibitors name, targets, structure and formula.

Name Targets IC50 for VEGFR Targeting Structure and Formula Refs.

Sunitinib VEGFR-2, FLT3, c- VEGFR-2: 80 nM

[157]
[SU11248] Kit, PDGFRβ [cell-free assays]

C22H27FN4O2

VEGFR-2, VEGFR-
Sorafenib 3, Raf-1, B-Raf, B- VEGFR-2: 90 nM
[BAY 43- Raf [V599E], VEGFR-3: 20 nM [169]
9006] mPDGFRβ, FLT3, c- [cell-free assays]
Kit, FGFR1

C21H16ClF3N4O3

VEGFR-2: 40 nM
Vandetanib VEGFR-2, VEGFR-
VEGFR-3: 110 nM [179]
[ZD6474] 3, EGFR
[cell-free assays]
C22H24BrFN4O2

Apatinib VEGFR-2: 1 nM
VEGFR-2, RET [194]
[YN968D1] [cell-free assays]

C24H23N5O

Cabozantinib
VEGFR-2, c-Met, VEGFR-2: 0.035 nM
[XL184,
Ret, Kit, Flt-1/3/4, [188]
BMS- [cell-free assays]
Tie2, and AXL
907351]

C28H24FN3O5

VEGFR-1/FLT1,
Foretinib VEGFR-3/FLT4, VEGFR-1: 6.8 nM
[GSK136308 Met, KDR, Tie-2, VEGFR-3: 2.8 nM [208]
9] RON, FLT3, PDG- [cell-free assays]
FRα, Kit, PDGFRβ

C34H34F2N4O6

VEGFR-2: 100-200 nM
PD173074 VEGFR-2,FGFR1 [227]
[cell-free assay]

C28H41N7O3
(Table 2) contd…
902 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 Malekan and Ebrahimzadeh

Name Targets IC50 for VEGFR Targeting Structure and Formula Refs.

Semaxanib VEGFR-2: 13 nM
VEGFR-2/Flk1 [203]
[SU5416] [cell-free assays]

C15H14N2O

Ponatinib VEGFR-2, Abl, VEGFR-2: 1.5 nM

PDGFRα, FGFR1, c- [223]
[AP24534] Src, c-Kit [cell-free assay]

C29H27F3N6O
VEGFR-2/KDR,
VEGFR-3/FLT4,
FLT3, RET, Aurora
A, Src,
NTRK1/TRKA, VEGFR-2: 58.2 nM
ENMD-2076 CSF-1R/c-Fms, VEGFR-3: 15.9 nM [216]
LCK, FAK, PDG- [cell-free assays]
FRα, BLK, FGFR2,
YES1, Abl1 [T315I],
FGFR1, Fyn, JAK2, C21H25N
Kit, Aurora B

VEGFR-1: 380 nM
Brivanib
VEGFR-1, VEGFR- VEGFR-2: 25 nM
[BMS- [212]
2, Flk1, FGFR1 [Human umbilical vein endo-
582664]
thelial cells]

C19H19FN4O3

PFS or overall survival [OS] compared with docetaxel
alone, while the number of common adverse events was
higher in the combined regimen [166]. Another prospective,
randomized phase III trial was done by Crown et al. to ex-
amine sunitinib in combination with capecitabine versus
capecitabine monotherapy. They conducted the study on
442 cases with heavily pretreated metastatic BC allocated
into two groups included 221 patients in each, sunitinib plus
capecitabine group [median age of 52 years old] and cape-
citabine monotherapy group [median age of 54 years old].
In the combination arm, orally capecitabine administrated
2,000 mg/m2 [1,000 mg/m2 twice daily] on days 1 to 14 of a
3-week cycle combined with sunitinib at a dose of 37.5 mg
once daily. In the monotherapy arm, patients only received
capecitabine a dose of 2,500 mg/m2 [1,250 mg/m2 twice
daily]. They found out sunitinib's addition to capecitabine
does not increase clinical outcomes of patients with meta-
static BC. Of note, they reported that the frequency of he-
matological adverse events was higher and more severe in
the sunitinib group, neutropenia [31% vs. 4%] and thrombo-
cytopenia [17% vs. 0%] [167]. Similarly, Barrios et al. also
reported a randomized, open-label phase III trial of sunitinib
versus capecitabine in previously treated HER2-negative
advanced BC patients. Their final data indicated that PFS
was lower with sunitinib than capecitabine, and also
sunitinib approach was correlated with higher frequencies
and greater severity of many common adverse events [168].
6.2.2. Sorafenib [BAY 43-9006]
Sorafenib inhibits VEGFR-2 and VEGFR-3 with IC50
of 90 nM, 20 nM, respectively, in cell-free assays [169].
The anti-tumor activity of this molecule was studied in pre-
clinical studies [170, 171]. Zanotto-Filho et al. declared that
sorafenib blocks induced inflammation, invasion, and angi-
ogenesis in BC cells by promoting alkylating therapy [172].
Besides, Sui et al. observed that the synergistic chemothera-
peutic effect of sorafenib could be highly efficient against
murine breast carcinoma in vivo and in vitro [173].
Isaacs et al. conducted a phase I/II trial to evaluate so-
rafenib's performance to overcome the resistance in aroma-
tase inhibitor-resistant metastatic BC patients. Cases were
35 postmenopausal females with hormone receptor-positive
BC. The study's first primary and secondary objectives were
VEGFRs as a Target in Breast Cancer
CBR and toxicity, respectively. Sorafenib 400 mg twice
daily was prescribed as the phase II dose. The results
showed a CBR of 23% for the combination of sorafenib and
anastrozole, which was encouraging. Also, a significant
toxicity rate, including fatigue, diarrhea, nausea, and hand-
foot syndrome as the most common adverse events, was
observed in patients. They recommend that future trials
could examine lower doses of sorafenib due to its level of
side effects [174]. In addition, sorafenib was assessed in a
phase II study in metastatic BC patients who had previously
received anthracyclines or taxanes. The primary end-point
was tumor response rate. They registered 23 cases [median
age of 54 years old], 22 out of 23 had prior anthracycline
therapy and 16 out of 23 revived prior taxane drugs. Soraf-
enib was received as 400 mg/twice-daily on days 1 through
28 of each 4-week cycle. They found that monotherapy with
sorafenib did not induce a significant tumor response, alt-
hough it was well tolerated [175]. Mina and her colleagues
evaluated the efficacy and safety of bevacizumab plus so-
rafenib as dual angiogenesis blockades in metastatic BC.
They arranged the regimen with bevacizumab intravenously
5 mg/kg weekly plus sorafenib 200 mg as a single oral dose
daily. It is concluded that this regimen has substantial tox-
icity and minimal efficacy. They also expressed that further
study of this combination is not advised [176].
Recently Mavratzas et al. carried out a randomized,
double-blind, placebo-controlled phase II trial, investigated
sorafenib in combination with docetaxel as the first-line
cure for women with HER2-negative metastatic BC. Ninety-
eight patients who participated in this study received docet-
axel 100 mg/m2 on day one every three weeks and sorafenib
400mg bid or placebo on days 2-18 each cycle till unac-
ceptable toxicity or tumor progression occurred. They
showed that this approach not only failed to enhance PFS
but also increased toxicity [177]. In 519 metastatic HER2-
negative BC patients, sorafenib plus capecitabine was stud-
ied by Baselga et al. as a phase III trial. They prescribed
sorafenib 600 mg/day orally administered at starting dose
and 400 mg BID at dose escalation. The primary end-point
was PFS. They achieved that sorafenib's addition to capecit-
abine did not improve PFS, OS, or ORR. In addition, toxici-
ty was higher in the sorafenib arm than in the placebo arm
[178].
6.2.3. Vandetanib [ZD6474]
Vandetanib is a potent inhibitor of VEGFR-2 with IC50
of 40 nM in a cell-free assay. It also inhibits VEGFR-3 with
IC50 of 110 nM [179]. Anti-tumor activity of vandetanib
has been preclinically assessed in various tumor cell lines
such as prostate cancer cell lines and BC cells [180-182]. By
conducting a study on BC cell lines, Sarkar et al. declared
that vandetanib with phototherapy [UV-B] could be an al-
ternative approach for treating infiltrating metastatic BC
cells [182].
A phase I trial was conducted to test the combination of
vandetanib and metronomic cyclophosphamide and metho-
trexate in metastatic BC. All participants received
vandetanib daily in 3 dose-escalation cohorts [100 mg, 200
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 903
mg, and 300 mg], cyclophosphamide 50 mg daily, and
methotrexate 2.5 mg on days 1 and 2 of each week. They
ascertained vandetanib was tolerable at a maximum dose of
200 mg, and relatively low clinical activity was observed in
the population [183]. Miller et al. appraised the efficacy and
safety of vandetanib in 46 patients with previously treated
metastatic BC. The primary end-point was ORR. Subjects
were enrolled into one of the two cohorts, 100 or 300 mg
orally once daily. They set 28 days as one cycle and con-
cluded that vandetanib monotherapy was well tolerated from
their multicenter phase II trial, but there were no objective
responses. Only one patient in the 300 mg group had stable
disease for ≥24 weeks. Diarrhea and rash were the most
common adverse events, and 7 patients out of 24 in the 300
mg cohort showed asymptomatic prolongation of the QTc
interval [grade 1] [184].
Boér et al. reported a double-blind, placebo-controlled,
randomized phase II study to investigate the effects of
vandetanib with docetaxel in patients with advanced BC.
They enrolled 64 patients, 35 patients [mean age of 54
years] into the docetaxel plus vandetanib group, and 29 pa-
tients [mean age of 57 years] into the docetaxel plus placebo
group. They arranged the study as once-daily oral
vandetanib [100 mg] and inter venular, every 21 days of
docetaxel [100 mg/m2] compared to placebo plus docetaxel.
They finally reported that vandetanib plus docetaxel was
generally well-tolerated, but the clinical response was not
different from placebo plus docetaxel. Neutropenia, alope-
cia, stomatitis, and diarrhea were reported as the most com-
mon adverse events [185]. Moreover, Fulvestrant plus
vandetanib was studied in a phase II trial by Clemons and
his colleagues. They registered 133 postmenopausal women
with bone-only or bone predominant, HR-positive metastat-
ic BC. They prescribed vandetanib 100 mg orally once daily
and fulvestrant 500 mg intermuscular injection on days 1,
15, 29, then monthly. In conclusion, it was reported that
vandetanib plus fulvestrant did not improve PFS and OS in
patients [186].
6.2.4. Cabozantinib [XL184, BMS-907351]
Cabozantinib is a super-potent VEGFR-2 inhibitor with
an IC50 of 0.035 nM in a cell-free assay [187]. Several pre-
clinical studies were performed to examine the anti-tumor
activity of this molecule [188, 189]. It is determined that
cabozantinib via VEGFR blockade regresses tumor angio-
genesis, reduces tumor metastasis, and enhances intratumor-
al hypoxia and apoptosis [188].
Tolaney et al. conducted a phase II trial with 35 patients
who received cabozantinib 60 mg daily on a 3-week cycle.
Their results showed that ORR was 9%. Additionally,
cabozantinib's therapeutic benefits and favorable safety in
metastatic TNBC patients were achieved. In terms of toxici-
ties, fatigue [77%], diarrhea [40%], oral mucositis [37%],
and palmar-plantar erythrodysesthesia [37%] were the most
common side effects, including all grades [190]. Tolaney
and her colleagues, in another phase II trial, which was a
placebo-controlled randomized discontinuation study, inves-
tigated cabozantinib in metastatic breast carcinoma. Patients
904 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
received cabozantinib 100 mg daily during a 12-week lead-
in stage. They observed that cabozantinib exhibited clinical
activity in heavily pretreated patients with an ORR of 13.6%
and week 12 DCR of 46.7%. These results assumed encour-
aging and further experimentation of cabozantinib is rec-
ommended. Palmar-plantar erythrodysesthesia, hyperten-
sion, fatigue, abdominal pain, dyspnea, asthenia, and in-
creased aspartate aminotransferase were reported as the
most frequent grade ≥3 side effects in this study [191].
Thirty-five metastatic TNBC patients entered in a pro-
spective single-arm, single-center phase II clinical trial
aimed to assess the efficacy of cabozantinib. Finally, they
assessed the results of the study only by 30 patients. De-
creased tumor density [≥15%] at first follow-up was seen in
22 [73%] patients. Furthermore, they observed that the clin-
ical benefit rate [CBR] was 40% by response evaluation
criteria in solid tumors 1.1 [RECIST1.1] and 73% by Choi
response criteria [192]. Leone et al. tested cabozantinib into
two different conditions, cabozantinib alone, and in combi-
nation with trastuzumab. This single-arm phase II study was
conducted with 36 BC patients with brain metastases. Sub-
jects underwent cabozantinib 60 mg daily on a 21-day cycle.
They concluded that cabozantinib has antivascular effects
but insufficient antitumoral activity in these patients. The
most common reported adverse events were fatigue, in-
creased aspartate aminotransferase, constipation, and nausea
[all grades]. Also, there were some grade 3 adverse events,
including elevated aminotransferase, hyponatremia, and
thromboembolic events [193].
6.2.5. Apatinib [YN968D1]
Apatinib is an excellent inhibitor of the VEGF signaling
pathway with IC50 values of 1 nM for VEGFR-2 in a cell-
free assay [194]. Preclinical studies showed that apatinib has
different positive effects against tumor cells, including pro-
liferation and invasion suppression and enhancement of
chemotherapy efficacy [195-197]. These effects were also
tested in various types of cancerous tissues such as leukemia
and BC cells [196, 198]. Apatinib has been widely investi-
gated in clinical trials [199]. Hu et al. conducted a multicen-
ter phase II trial to clinically test apatinib in 38 metastatic
non-TNBC. Patients received 500 mg daily on days 1
through 28, of each 4-week cycle. The primary endpoint
was PFS, and secondary endpoints were ORR, DCR, OS,
toxicity. They observed that apatinib has objective efficacy
in heavily pretreated cases with manageable toxicity. The
most frequent grade 3 and 4 treatment-related side effects
were reported hypertension [20.5%], hand-foot syndrome
[10.3%], and proteinuria [5.1%] [200].
Fan et al. reported two open-label, single-arm, multicen-
ter phase II studies. They stated apatinib shows strong anti-
tumor activity in 80 advanced BC cases who received apa-
tinib [750 or 500 mg/day orally in 4-week cycles] [201]. A
single-arm, single-center prospective phase II study enrolled
17 patients with stage II/III advanced TNBC. They exam-
ined apatinib in dosage of 250 mg per day in combination
with dose-dense paclitaxel and carboplatin. As a result, they
reported that apatinib as neoadjuvant therapy is useful and
Malekan and Ebrahimzadeh
well-tolerated in these patients. They reported that grade
III/IV of each neutropenia, thrombocytopenia were observed
in 3 cases, and anemia, fatigue, arrhythmia, and alanine
aminotransferase [ALT] elevation were observed in 1 case
[202].
6.2.6. Semaxanib [SU5416]
Semaxanib is an exclusive and selective VEGFR-2 in-
hibitor with an IC50 value of 1.23 μM in a cell-free assay
[203]. The preclinical investigation revealed the anti-tumor
effects of this molecule [204]. Furthermore, Overmoyer et
al. tested semaxanib in 18 patients with inflammatory BC.
Patients received semaxanib, 110 mg/m2 given on days 1
and 4 every three weeks, plus doxorubicin 60 mg/m2 ad-
ministered on day 1 every three weeks. They reported unfa-
vorable cardiac interactions between patients [205].
Semaxanib [SU5416] was prepared from commercially
available 3,5-dimethylpyrrol-2-carboxaldehyde by aldol
condensation with indolin-2-one in ethanol in the presence
of piperidine in reflux condition for 3 h. [57%] (Scheme 1)
[206].
N
a H
O OHC N
N O
H H N
H
Semaxanib (SU5416)
a. Piperidine/ethanol/reflux/3-5 h.
Scheme 1. Preparation of Semaxanib [SU5416].
The preliminary analysis suggested that the relative po-
tency and selectivity of these compounds for inhibition of
kinases may be sensitive to the Z-E configurations. The 3-
substituted indolin-2-ones may exist as either the Z or E
isomer depending on the characteristics of the substituents
at the C-3 position of the 3-substituted indolin-2-one posi-
tion and the proton[s] in the C-3 substitution of the 3-
substituted indolin-2-ones. Semaxanib analogues containing
a pyrrole substituent at the C-3 position of the 3-substituted
indolin-2-ones existed exclusively as the Z isomer forms.
Methylation at the N-1´ position of the pyrrole resulted in a
compound that existed as an E isomer and was shown to be
a weak inhibitor of the RTK. Substitution at the C-4 position
of the indolin-2- one ring was found to have a negative im-
pact on the inhibitory activity of compounds when tested
against RTK activities. Electron-withdrawing substituents
such as chloro, fluoro or nitro at the C-5 position of the in-
dolin-2-ones may be detrimental to inhibitory activities as-
sociated with RTK inhibitors.
Inhibitory activities associated with compounds having
small alkyl and electron-withdrawing polar moieties at both
the C-3´ and C-4´ positions in the pyrrole ring were found to
be either highly selective or specific toward the VEGF [Flk-
1] RTK. Most of the compounds with substitutions at the C-
3´ and C-5´ positions in the pyrrole ring of Semaxanib
maintained the good inhibitory activity against the VEGF
[Flk-1] RTK activity. Proton at the N-1 position of the in-
VEGFRs as a Target in Breast Cancer
O O
O O
i, ii
HO Cl O NO 2
1 2
OH
iv O v, vi
Cl O N
4 5
F NO 2
vii O viii
O
O N O N
6 7
Reagents and conditions: (i) Br(CH 2)3Cl, acetone, 0
30 min, rt., 12 h; (ii) 98%HNO3, CH 2Cl 2, 0 oC, 4 h;
(iii) DMF-DMA, toluene, 110 oC, 10 h; (iv) Fe powder, HOAc, rt., 30 min, 80 oC, 2 h;
(v) Morpholine, CH 3CN, 85 oC, 10 h; (vi) POCl 3, 85 oC, 6 h; (vii) 2-fluoro-4-nitrophenol, PhCl, 140 oC, 30 h;
(viii) Fe powder, NH 4Cl (cat.), EtOH/H 2O, reflux, 5 h.
Scheme 2. Preparation of the key intermediate of 6,7-disubstituted-4- phenoxyquinoline for the preparation of Foretinib [GSK1363089].
dolin-2-ones is essential for the inhibitory activity against
the RTKs. Vinyl proton is critical for 3-substituted indolin-
2- ones to inhibit the RTKs. In this series, indolin-2-one
core was shown to occupy a site in which the adenine of
adenosine triphosphate binds and the substituents around the
indolin-2-one core were shown to extend into the hinge re-
gion between the two kinase lobes [206].
6.2.7. Foretinib [GSK1363089]
Foretinib can suppress VEGFR-1 and VEGFR-3 with
IC50 of 6.8 nM and 2.8 nM in cell-free assays, respectively
[206]. Examination of this molecule on cancerous cell lines
showed positive effects on tumor growth inhibition [207].
Rayson et al. conducted a single-arm, multicenter phase II
trial to determine the efficacy of single-agent foretinib in
patients with TNBC. They administered foretinib 60 mg
orally and daily to enrolled patients, in a 2-stage single-arm
trial. They reported that this approach did not reach its pri-
mary end-point. However, the clinical benefit rate was ob-
served at about 46%, therefore it may have helpful clinical
activity as a single, non-cytotoxic agent in patients [208].
Moreover, foretinib was investigated in combination with
other molecules such as lapatinib. Chia and his colleagues in
a phase I study of lapatinib plus foretinib enrolled 19 HER2-
positive metastatic BC patients. They reported limited clini-
cal activity for this combination in the enrolled cases. Also,
they reported that diarrhea, fatigue, anorexia, and nausea are
possible adverse events [209]. The synthesis of the key in-
termediates of 6,7-disubstituted-4- phenoxyquinolines 7 for
preparation of Foretinib [GSK1363089] was achieved in 8
steps from the commercially available 1-[4-hydroxy-3-
methoxyphenyl]ethanone 1 as shown in Scheme 2.
Starting material 1-[4-hydroxy-3-methoxyphenyl] etha-
none 1 was alkylated with 1- bromo-3-chloropropane in
acetone under basic condition to provide compound 2,
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 905
O
iii O
N
Cl O NO 2
3
Cl
O
O N O N
F NH 2
O
O
O N O N
oC,
which was converted to nitro compound 3 using fuming
nitric acid as nitration reagent in dichloromethane at 20 °C
for 6 h with 70% yield. Next, condensation of 3 with di-
methyl formamide dimethyl acetal [DMF-DMA] in reflux-
ing toluene afforded yellow solid, which was reduced and
cyclized using glacial acetic acid and iron powder to provide
hydroxyquinoline 4 with a high yield and purity. Substitu-
tion of 4 with excessive morpholine in acetonitrile at reflux
provided intermediates, which were treated with phosphorus
oxychloride to afford chloroquinoline 5. The obtained com-
pound 5 was etherified with 2-fluoro-4-nitrophenol in chlo-
robenzene to obtain purified compound 6 which were re-
duced using iron powder and catalytic amounts of ammoni-
um chloride in ethanol to obtain amide 7 [210].
Recently, significant progress has been made in the de-
velopment of small-molecule c-Met inhibitors, which such
as Foretinib. Most of them bearing 6,7-disubstituted- 4-[2-
fluorophenoxy]quinoline pharmacophores and have multi-
targeted tyrosine kinase inhibitory activity. As shown in Fig.
(2), the structure-activity relationships [SARs] of 6,7-
disubstituted-4-[2-fluorophenoxy]quinoline based inhibitors
suggested that quinoline pharmacophores were responsible
for forming hydrogen bonds with the backbone of c-Met
kinase, and an aryl fragment [moiety B] probably extended
into the hydrophobic pocket. These 6,7-disubstituted-4-[2-
fluorophenoxy] quinoline derivatives have two obvious
structural characteristics in their linkers between moiety A
and moiety B which is known as ‘5 atoms regulation/
hydrogen-bond donors or acceptors’. These structural fea-
tures indicated that exploring a satisfactory linker was a
practicable way of designing new quinolone derivatives
[211].
6.2.8. Brivanib [BMS-582664]
Brivanib is an ATP-competitive inhibitor against
VEGFR-2 with IC50 of 25 nM, moderate potency on
906 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 Malekan and Ebrahimzadeh

5-atome linker
A moiety B moiety
H H
F N N

O O O F
O

O N O N
Different substitued phenyl
D

Different cyclic teitiary amines such as: piperidinyl, pyrrolidinyl,

4-methyl piperidinyl and 4-methyl piperazinyl

Fig. (2). A brief SAR for the 6,7-disubstituted-4-[2-fluorophenoxy]quinoline derivatives including foretinib.

Me OPh X
Me HN
N a,b Me d,e
HO HO NH
N N
N N
1 HO
2, X = OH F 4
c
3, X= Cl
HN
Me HN
Me

Me O Me
F Me O
N f F
HO HO
N O N
N N
N
5 Brivanib (BMS-582664)

Reagents and reaction conditions: (a) benzyl bromide, K2CO 3, 70 °C; (b) 1 N HCl, 80 °C, 64%, two steps; (c)
POCl3, 110 °C; (d) DMF, NaH, 76%, two steps; (e) 10% Pd/C, HCOONH 4, DMF, 86%; (f) (R)-(+)- propylene
oxide, Et3N, EtOH, 70 °C, 53%

Scheme 3. Preparation of Brivanib [BMS-582664].

VEGFR-1 with IC50 of 380 nM [212]. Studies revealed that
brivanib has the potential of tumor growth inhibition, such
as human hepatocellular carcinoma and BC cell lines [213,
214]. Schöffski et al. conducted a phase II randomized trial
of brivanib in patients with advanced solid tumors. They
reported that objective responses were seen in ovarian,
breast, and gastric/esophageal cancer [215]. The reaction
sequence for the preparation of Brivanib [BMS-582664] is
detailed in Scheme 3. The 6-position phenol 1 was first pro-
tected as a benzyl ether by treatment with benzyl bromide
and K2CO3 in acetonitrile. The resulting intermediate was
heated in aqueous HCl at 80 °C to remove the phenyl ether
protecting group at the 4-position to obtain 2 over two steps.
The 4-oxo group was converted to chloroimidate 3 by
treatment with POCl3 at 110 °C. Reaction of 3 with 4 in
DMF in the presence of NaH and hydrogenolysis of the re-
sulting intermediate with ammonium formate and 10% pal-
ladium on carbon afforded the compound 5. Treatment of 5
with [R]-[+]-propylene oxide in ethanol at 70 °C in the
presence of triethylamine afforded BMS-582664 with high
optical purity [99.5% ee] [212].
Based on the structure-activity relationship studies
[SAR], a methyl group at the 5-position and a substituted
alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]
triazine core gave potent compounds. It was observed that
the compounds with a 6-hydroxy substituent showed good
enzyme potency. The ester at the 6-position was converted
to a hydroxyl group. These phenols are potent kinase inhibi-
tors, but show poor plasma exposure upon oral administra-
tion. The phenol was alkylated with different groups to af-
ford the series of 6-position ethers. Substitution at R6 af-
fected kinase activity only marginally but allowed modula-
tion of aqueous solubility, pharmacokinetic properties, and
the in vitro safety profile. Compounds containing an amine,
alcohol, or ether group on the R6 tether were potent against
the VEGFR-2 enzyme, whereas analogues containing a sul-
fone or a sulfonamide exhibited moderate potency. The in-
corporation of a methyl group at the 5-position gave optimal
potency against the VEGFR-2 enzyme. Although the intro-
duction of a methyl group at the 2-position of the indole ring
did not affect the potency, the introduction of a fluorine
group at the 4-position of the indole ring gave a 4-fold in-
VEGFRs as a Target in Breast Cancer
O
CHO
N a
HN 2 N NH 2
CN
1 2
b,c HN
N
a. EtOCH 2CH 2O-Na+, reflux; b,NaH, DMF; c, t-Bu-N=C=O, r.t.
Scheme 4. Preparation of PD173074.
crease in potency against VEGFR-2. Compounds with an
amino group on the side chain possessed reduced potency
against the hERG ion channel [212].
6.2.9. ENMD-2076
ENMD-2076 is a selective inhibitor of VEGFR-3 and
VEGFR-2 with IC50 of 15.9 nM and 58.2 nM in cell-free
assays [216, 217]. Preclinical studies tested ENMD-2076 in
different tumor models, including BC models [218, 219].
Diamond et al. declared that ENMD-2076 showed robust
anti-tumor activity in TNBC models [219].
Afterward, Diamond et al. conducted a phase II clinical
trial to investigate the efficacy of ENMD-2076 in TNBC
patients. They enrolled 41 TNBC subjects and provided
them with ENMD-2076 [250 mg orally administered daily,
with continuous dosing in 4-week cycles]. Finally, it was
determined that ENMD-2076 has partial clinical benefit
lasting more than six months in 16.7% of patients with pre-
treated metastatic conditions, as single-agent therapy [220].
6.2.10. Other Selective-VEGFR Inhibitors
Ponatinib and PD173074 are selective-VEGFR inhibi-
tors investigated in BC cell lines, which have not been test-
ed in human trials so far [221, 222]. Ponatinib [AP24534] is
a novel and potent suppressor of VEGFR-2 with IC50 of 1.5
nM in a cell-free assay [223, 224]. Shao et al. declared that
ponatinib has a suppression potential in BC lung metastasis.
Indeed, ponatinib inhibits the expression of metastasis-
related genes mainly via the ERK/c-Jun signaling axis
[221]. PD173074 is an inhibitor of VEGFR-2 with IC50 of
100-200 nM in a cell-free assay [225]. Ye et al. used
PD173074 in the human BC cell lines, MDA-MB-468,
MDA- MB-453, MDA-MB-361, MDA-MB-231, MCF-7,
and the murine mammary tumor cell line 4T1. They con-
cluded that this molecule has the potential of inhibiting BC
growth and metastasis [222].
Scheme 4 shows the synthetic route used to prepare
PD173074. The condensation of aldehyde 1 with an ary-
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 907
O
N O
O HN 2 N N NH 2
3
O
N O
N N NH
O NH
PD173074
lacetonitrile 2 under basic conditions afforded the corre-
sponding 2,7-diamino-6 arylpyrido[2,3-d]pyrimidine inter-
mediate 3. Treatment of 3 with sodium hydride in DMF
followed by the addition of the corresponding isocyanate to
the reaction mixture afforded the ureas, PD173074.
Three regions of the parent molecule were targeted for
initial SAR studies. Modifications were made to the 2-, 6-,
and 7-positions of the initial lead compound PD173074. It
was found that disubstitution at the ortho positions of the
phenyl ring by small groups such as 2´,6´-dichloro and
2´,6´-dimethyl resulted in a general increase in TKI activity
relative to the unsubstituted compound [approximately 10-
fold more potent]. Larger groups in the ortho positions such
as ethyl or methoxy resulted in decreased TKI activity
across the panel of kinases tested. Ortho substitution re-
stricts the phenyl group to an orthogonal conformation with
respect to the pyrido[2,3-d] pyrimidine ring. The 2´,3´,5´,6´-
tetramethyl phenyl, and 3´,5´-dimethoxy phenyl showed
good selectivity relative to the tyrosine kinases. Overall,
optimization of phenyl substituents in the 6-position led to
only slight increases in TKI potency beyond that of the ini-
tial lead. To improve the poor aqueous solubility of the
compound, several sites on the molecule were targeted for
attaching aminoalkyl side chains. the 3-[diethylamino] pro-
pyl side chain was found to afford enhanced TKI and c-src
tyrosine kinases as well as improved aqueous solubility rela-
tive to the lead compound. The incorporation of a 2-
alkylamino side chain generally resulted in enhanced TKI
potency, aqueous solubility, and bioavailability relative to
the parent compound. SAR work focusing on understanding
the contribution of the urea functionality of compound re-
vealed the need for a mono N´-substituted alkylurea group
in the 7-position of the pyrido[2,3-d]pyrimidine nucleus for
good tyrosine kinase inhibitory activity. A variety of alkyl-
or aryl ureas were well tolerated in this position. However,
larger groups such as adamantylurea resulted in an overall
decrease in activity. The urea functionality had little effect
on the tyrosine kinase selectivity profile in this series, but
was necessary for good TKI potency [225].
908 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 Malekan and Ebrahimzadeh

O 2N O 2N H 2N
a N b N c
Br N N

CF3 1 CF3 2 CF3 3

H
N N N
N g
O N N N
N N
4 8
CF3

f
H
N
N
N N e N
d O N
N N N
N N N
Br H CF3
5 6 7
9, Ponatinib (AP24534)
SiMe3

Reagents and conditions: a, 1-methylpiperazine, Et3N, CH 2Cl 2, rt; b, Na 2S2O 4, acetone/water, reflux; c, 4-
methylbenzoyl chloride, (i-Pr) 2NEt, THF, rt; d, Br 2, EtOH, rt; e, trimethylsilylacetylene, 5 mol% Pd(PPh 3)2Cl 2,
7.5 mol%CuI, (i-Pr) 2NEt, DMF, 80 oC; f, TBAF, THF, rt; g, 5 mol%Pd(PPh 3)4, 7.5 mol%CuI, (i-Pr) 2NEt, DMF, rt;

Scheme 5. Preparation of ponatinib.

Table 3. Ongoing clinical trials on pan-VEGFR and selective-VEGFR inhibitors.

Number of Ongoing
Name Status Phase NCT Numbers
Studies
Pazopanib 1 ANR: 1 Phase 1: 1 NCT01407562
Pan-VEGFR inhibitors

ANR: 1 Phase 1 and 2: 2 NCT01116648, NCT0490567,

Cediranib 4
R: 3 Phase 2: 2 NCT02484404, NCT02498613

Regorafenib 1 EBI: 1 Phase 2: 1 NCT02955940

Phase 1: 1
NCT02562118, NCT04427293,
Lenvatinib 3 R: 3 Phase 1 and 2: 1
NCT03797326
Phase 2: 1
Phase 1: 1
NCT01724606, NCT00499525,
Sorafenib 3 ANR: 3 Phase 2: 1
NCT01621906
Not Applicable: 1
Selective-VEGFR inhibitors

Phase 1: 2 NCT03580395, NCT03982485,

NYR: 2 Phase 2: 7 NCT04722718, NCT02768415,
R: 9 Phase 2 and 3: 1 NCT03775928, NCT03932526,
Apatinib 14 NCT04335006, NCT03254654,
ANR: 2 Phase 3: 2 NCT04296370, NCT03075462,
EBI: 1 Phase 4: 1 NCT04303741, NCT03945604,
Not Applicable: 1 NCT03475589, NCT04510532

ANR: 3 Phase 1: 1 NCT03316586, NCT01441947,

Cabozantinib 5 Phase 1 and 2: 1 NCT02260531, NCT04514484,
R: 2 Phase 2: 3 NCT03170960
Date of search: 4/19/2021; Source of data: clinicaltrials.gov; Not yet recruiting [NYR]: The study has not started recruiting participants; Recruiting [R]: The study is currently
recruiting participants; Enrolling by invitation [EBI]: The study is selecting its participants from a population, or group of people, decided on by the researchers in advance. These
studies are not open to everyone who meets the eligibility criteria but only to people in that particular population, who are specifically invited to participate; Active, not recruiting
[ANR]: The study is ongoing, and participants are receiving an intervention or being examined, but potential participants are not currently being recruited or enrolled.

The syntheses of inhibitors bearing triple-bond structural group, deprotection with either tetrabutylammonium fluo-
motifs [ponatinib] were based on a tandem Sonogashira ride or potassium carbonate/methanol.
coupling strategy. Initially, the heteroaryl bromides 6 as
Scheme 5 illustrates the synthesis of inhibitor 9
coupling partners in the first Sonogashira reaction (Scheme [ponatinib]. Selective bromination of 5 furnished yields
5). The second step involves cleavage of the trimethylsilyl bromide 6. Direct Sonogashira reaction of 6 with trime-
VEGFRs as a Target in Breast Cancer
Fig. (3). Classification of discussed agents based on the available investigations. (A higher resolution / colour version of this figure is availa-
ble in the electronic copy of the article).
thylsilylacetylene afforded the desired coupling product 7.
Subsequent desilylation furnished terminal alkyne 8, which
was coupled with benzamide 4 to yield 9 [ponatinib].
In the ponatinib series, minor structural modifications to
either the acetylene linker, the methylpiperazinyl moiety, or
the trifluoromethyl group significantly affected potency
while modifications or even deletion of one of these binding
elements still yielded potent native inhibitors. In confirming
the absolute requirement of the carbon-carbon triple bond
for potency, both the double bond linked and fully saturated
molecules significantly reduced activity [224].
One unusual structural feature of this potent inhibitor is
the inflexible acetylene linkage connecting the heterocycle
core serving as the hinge binder and the N-arylbenzamide
occupying the hydrophobic selectivity Pocket [226, 227].
This rigid, less sterically demanding linker enables binding
to the enlarged Ile315 side chain of the T315Imutant and
correctly directs both inhibitor segments into well-defined
binding pockets making more productive interactions with
the protein. Another key structural element required for
achieving high potency is the hybrid N-arylbenzamide,
which allows cooperative molecular exploitation of both
trifluoromethyl and piperazinyl groups and causes van der
Waals and hydrogen-bonding interactions with the protein.
In general, the piperazine tail confers excellent cellular po-
tency and improved aqueous solubility with reduced plasma
protein binding, leading to favorable pharmacokinetic prop-
erties following oral dosing in rats and mice [224].
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 909
7. ONGOING CLINICAL TRIALS ABOUT VEGFR
INHIBITOR MOLECULES IN BC
Ongoing studies are defined in four status groups i] not
yet recruiting, ii] recruiting, iii] enrolling by invitation, and
iv] active, not recruiting. We summarized registered availa-
ble projects that are using VEGFR inhibitors on BC patients
in Table 3.
CONCLUSION AND FUTURE DIRECTIONS
As in most tumors, angiogenesis plays a crucial role in
the tumorigenesis of BC. Thus, antiangiogenic therapeutic
approaches based on the interruption of VEGF/VEGFR sig-
naling via selective and pan-VEGFR inhibitors could be
efficient and helpful. The interest in designing and synthe-
sizing small molecule inhibitors has increased in the past
two decades. Nowadays, not only attempts with the aim of
developing novel VEGFR inhibitors continue but also appli-
cation of the currently available molecules in different com-
binations with other drugs may exhibit some unexpected pro-
mising results. These attempts promise further exciting deve-
lopments, especially for BC treatment in the coming decade.
Based on the available reported results of pre-clinical
and clinical trials on BC treatment with these agents, it
might be possible to classify them into special groups,
which is exhibited in Fig. (3).
These data and classification should be interpreted with
caution since further studies are ongoing and the new stud-
910 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
ies may show different results and may prepare a more pre-
cise answer to the efficacy and safety of VEGFR inhibitors
in BC therapy. Ongoing and future well-designed trials may
better determine the optimal clinical application of these
inhibitors. However, many questions should be clarified.
For example, which one of monotherapy or adjuvant therapy
by these agents is more valuable? Why do are found some
controversial results for an agent in different studies and
methods? Are we sure now about the long-term side effects
of these inhibitors or not?
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Borri, F.; Granaglia, A. Pathology of triple negative breast cancer.
Semin. Cancer Biol., 2021, 72, 136-145.
http://dx.doi.org/10.1016/j.semcancer.2020.06.005 PMID:
32544511
[2] Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.;
Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of
incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J. Clin., 2018, 68(6), 394-424.
http://dx.doi.org/10.3322/caac.21492 PMID: 30207593
[3] Heer, E.; Harper, A.; Escandor, N.; Sung, H.; McCormack, V.;
Fidler-Benaoudia, M.M. Global burden and trends in premenopau-
sal and postmenopausal breast cancer: A population-based study.
Lancet Glob. Health., 2020, 8(8), e1027-e1037.
http://dx.doi.org/10.1016/S2214-109X(20)30215-1 PMID:
32710860
[4] Momenimovahed, Z.; Salehiniya, H. Epidemiological characteris-
tics of and risk factors for breast cancer in the world. Breast Can-
cer (Dove Med. Press)., 2019, 11, 151-164.
http://dx.doi.org/10.2147/BCTT.S176070 PMID: 31040712
[5] Aronson, K.J.; Miller, A.B.; Woolcott, C.G.; Sterns, E.E.;
McCready, D.R.; Lickley, L.A.; Fish, E.B.; Hiraki, G.Y.; Hol-
loway, C.; Ross, T.; Hanna, W.M.; SenGupta, S.K.; Weber, J.P.
Breast adipose tissue concentrations of polychlorinated biphenyls
and other organochlorines and breast cancer risk. Cancer Epi-
demiol. Biomarkers Prev., 2000, 9(1), 55-63.
PMID: 10667464
[6] Jagannathan, N.R.; Sharma, U. Breast tissue metabolism by mag-
netic resonance spectroscopy. Metabolites., 2017, 7(2), 25.
http://dx.doi.org/10.3390/metabo7020025 PMID: 28590405
[7] Stark, G.B.; Grandel, S.; Spilker, G. Tissue suction of the male
and female breast. Aesthetic Plast. Surg., 1992, 16(4), 317-324.
http://dx.doi.org/10.1007/BF01570694 PMID: 1414656
[8] Malhotra, G.K.; Zhao, X.; Band, H.; Band, V. Histological, mo-
lecular and functional subtypes of breast cancers. Cancer Biol.
Ther., 2010, 10(10), 955-960.
http://dx.doi.org/10.4161/cbt.10.10.13879 PMID: 21057215
[9] Eroles, P.; Bosch, A.; Pérez-Fidalgo, J.A.; Lluch, A. Molecular
biology in breast cancer: Intrinsic subtypes and signaling path-
ways. Cancer Treat. Rev., 2012, 38(6), 698-707.
Malekan and Ebrahimzadeh
http://dx.doi.org/10.1016/j.ctrv.2011.11.005 PMID: 22178455
[10] Folkman, J. Antiangiogenesis in cancer therapy--endostatin and its
mechanisms of action. Exp. Cell Res., 2006, 312(5), 594-607.
http://dx.doi.org/10.1016/j.yexcr.2005.11.015 PMID: 16376330
[11] Castañeda-Gill, J.M.; Vishwanatha, J.K. Antiangiogenic mecha-
nisms and factors in breast cancer treatment. J. Carcinog., 2016,
15(1), 1.
http://dx.doi.org/10.4103/1477-3163.176223 PMID: 27013929
[12] Matsumoto, T.; Mugishima, H. Signal transduction via vascular
endothelial growth factor (VEGF) receptors and their roles in ath-
erogenesis. J. Atheroscler. Thromb., 2006, 13(3), 130-135.
http://dx.doi.org/10.5551/jat.13.130 PMID: 16835467
[13] Ceci, C.; Atzori, M.G.; Lacal, P.M.; Graziani, G. Role of
VEGFs/VEGFR-1 signaling and its inhibition in modulating tumor
invasion: Experimental evidence in different metastatic cancer
models. Int. J. Mol. Sci., 2020, 21(4), 1388.
http://dx.doi.org/10.3390/ijms21041388 PMID: 32085654
[14] Zhang, Y.; Chen, Y.; Zhang, D.; Wang, L.; Lu, T.; Jiao, Y. Dis-
covery of novel potent VEGFR-2 inhibitors exerting significant
antiproliferative activity against cancer cell lines. J. Med. Chem.,
2018, 61(1), 140-157.
http://dx.doi.org/10.1021/acs.jmedchem.7b01091 PMID:
29189002
[15] Dar, A.A.; Goff, L.W.; Majid, S.; Berlin, J.; El-Rifai, W. Aurora
kinase inhibitors--rising stars in cancer therapeutics? Mol. Cancer
Ther., 2010, 9(2), 268-278.
http://dx.doi.org/10.1158/1535-7163.MCT-09-0765 PMID:
20124450
[16] Zhong, H.; Bowen, J.P. Molecular design and clinical develop-
ment of VEGFR kinase inhibitors. Curr. Top. Med. Chem., 2007,
7(14), 1379-1393.
http://dx.doi.org/10.2174/156802607781696855 PMID: 17692027
[17] Zhang, J.; Shan, Y.; Pan, X.; He, L. Recent advances in antiangio-
genic agents with VEGFR as target. Mini Rev. Med. Chem., 2011,
11(11), 920-946.
http://dx.doi.org/10.2174/138955711797068355 PMID: 21762098
[18] Grimm, D.; Wehland, M.; Pietsch, J.; Infanger, M.; Bauer, J.
Drugs interfering with apoptosis in breast cancer. Curr. Pharm.
Des., 2011, 17(3), 272-283.
http://dx.doi.org/10.2174/138161211795049723 PMID: 21348828
[19] Grimm, D.; Bauer, J.; Schoenberger, J. Blockade of neoangiogen-
esis, a new and promising technique to control the growth of ma-
lignant tumors and their metastases. Curr. Vasc. Pharmacol.,
2009, 7(3), 347-357.
http://dx.doi.org/10.2174/157016109788340640 PMID: 19601859
[20] Bergers, G.; Hanahan, D. Modes of resistance to anti-angiogenic
therapy. Nat. Rev. Cancer., 2008, 8(8), 592-603.
http://dx.doi.org/10.1038/nrc2442 PMID: 18650835
[21] Ferrara, N.; Houck, K.; Jakeman, L.; Leung, D.W. Molecular and
biological properties of the vascular endothelial growth factor
family of proteins. Endocr. Rev., 1992, 13(1), 18-32.
http://dx.doi.org/10.1210/edrv-13-1-18 PMID: 1372863
[22] Ellis, L.M.; Hicklin, D.J. VEGF-targeted therapy: Mechanisms of
anti-tumour activity. Nat. Rev. Cancer., 2008, 8(8), 579-591.
http://dx.doi.org/10.1038/nrc2403 PMID: 18596824
[23] Olsson, A-K.; Dimberg, A.; Kreuger, J.; Claesson-Welsh, L.
VEGF receptor signalling - in control of vascular function. Nat.
Rev. Mol. Cell Biol., 2006, 7(5), 359-371.
http://dx.doi.org/10.1038/nrm1911 PMID: 16633338
[24] Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of
the angiogenic switch during tumorigenesis. Cell., 1996, 86(3),
353-364.
http://dx.doi.org/10.1016/S0092-8674(00)80108-7 PMID:
8756718
[25] Zhang, W.; Zhu, C.; Wu, Y.; Ye, D.; Wang, S.; Zou, D.; Zhang,
X.; Kaplan, D.L.; Jiang, X. VEGF and BMP-2 promote bone re-
generation by facilitating bone marrow stem cell homing and dif-
ferentiation. Eur. Cell. Mater., 2014, 27(12), 1-11.
http://dx.doi.org/10.22203/eCM.v027a01 PMID: 24425156
[26] Rafii, S.; Lyden, D.; Benezra, R.; Hattori, K.; Heissig, B. Vascular
and haematopoietic stem cells: Novel targets for anti-angiogenesis
therapy? Nat. Rev. Cancer., 2002, 2(11), 826-835.
http://dx.doi.org/10.1038/nrc925 PMID: 12415253
VEGFRs as a Target in Breast Cancer
[27] Bruce, D.; Tan, P.H. Vascular endothelial growth factor receptors
and the therapeutic targeting of angiogenesis in cancer: Where do
we go from here? Cell Commun. Adhes., 2011, 18(5), 85-103.
http://dx.doi.org/10.3109/15419061.2011.619673 PMID:
22017472
[28] Neufeld, G.; Cohen, T.; Gengrinovitch, S.; Poltorak, Z. Vascular
endothelial growth factor (VEGF) and its receptors. FASEB J.,
1999, 13(1), 9-22.
http://dx.doi.org/10.1096/fasebj.13.1.9 PMID: 9872925
[29] Editor molecular biology of the VEGF and the VEGF receptor
family.Clauss, M., Ed.; Semin Thromb Hemost; Copyright© 2000
by Thieme Medical Publishers, Inc.: 333 Seventh Avenue, New,
2000.
[30] Mac Gabhann, F.; Popel, A.S. Dimerization of VEGF receptors
and implications for signal transduction: A computational study.
Biophys. Chem., 2007, 128(2-3), 125-139.
http://dx.doi.org/10.1016/j.bpc.2007.03.010 PMID: 17442480
[31] Bruce, D.; Tan, P.H. Blocking the interaction of vascular endothe-
lial growth factor receptors with their ligands and their effector
signaling as a novel therapeutic target for cancer: Time for a new
look? Expert Opin. Investig. Drugs., 2011, 20(10), 1413-1434.
http://dx.doi.org/10.1517/13543784.2011.611801 PMID:
21864224
[32] Joukov, V.; Pajusola, K.; Kaipainen, A.; Chilov, D.; Lahtinen, I.;
Kukk, E.; Saksela, O.; Kalkkinen, N.; Alitalo, K. A novel vascular
endothelial growth factor, VEGF-C, is a ligand for the Flt4
(VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EM-
BO J., 1996, 15(2), 290-298.
http://dx.doi.org/10.1002/j.1460-2075.1996.tb00359.x PMID:
8617204
[33] Achen, M.G.; Jeltsch, M.; Kukk, E.; Mäkinen, T.; Vitali, A.;
Wilks, A.F.; Alitalo, K.; Stacker, S.A. Vascular endothelial growth
factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF re-
ceptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc. Natl. Acad. Sci.
USA., 1998, 95(2), 548-553.
http://dx.doi.org/10.1073/pnas.95.2.548 PMID: 9435229
[34] Shibuya, M. Vascular endothelial growth factor receptor-1
(VEGFR-1/Flt-1): A dual regulator for angiogenesis. Angiogene-
sis., 2006, 9(4), 225-230.
http://dx.doi.org/10.1007/s10456-006-9055-8 PMID: 17109193
[35] Markovic-Mueller, S.; Stuttfeld, E.; Asthana, M.; Weinert, T.;
Bliven, S.; Goldie, K.N.; Kisko, K.; Capitani, G.; Ballmer-Hofer,
K. Structure of the Full-length VEGFR-1 extracellular domain in
complex with VEGF-A. Structure., 2017, 25(2), 341-352.
http://dx.doi.org/10.1016/j.str.2016.12.012 PMID: 28111021
[36] Fischer, C.; Mazzone, M.; Jonckx, B.; Carmeliet, P. FLT1 and its
ligands VEGFB and PlGF: Drug targets for anti-angiogenic thera-
py? Nat. Rev. Cancer., 2008, 8(12), 942-956.
http://dx.doi.org/10.1038/nrc2524 PMID: 19029957
[37] Waltenberger, J.; Claesson-Welsh, L.; Siegbahn, A.; Shibuya, M.;
Heldin, C-H. Different signal transduction properties of KDR and
Flt1, two receptors for vascular endothelial growth factor. J. Biol.
Chem., 1994, 269(43), 26988-26995.
http://dx.doi.org/10.1016/S0021-9258(18)47116-5 PMID:
7929439
[38] Gille, H.; Kowalski, J.; Yu, L.; Chen, H.; Pisabarro, M.T.; Davis-
Smyth, T.; Ferrara, N. A repressor sequence in the juxtamembrane
domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endo-
thelial growth factor-dependent phosphatidylinositol 3′-kinase ac-
tivation and endothelial cell migration. EMBO J., 2000, 19(15),
4064-4073.
http://dx.doi.org/10.1093/emboj/19.15.4064 PMID: 10921887
[39] Huang, K.; Andersson, C.; Roomans, G.M.; Ito, N.; Claesson-
Welsh, L. Signaling properties of VEGF receptor-1 and -2 homo-
and heterodimers. Int. J. Biochem. Cell Biol., 2001, 33(4), 315-
324.
http://dx.doi.org/10.1016/S1357-2725(01)00019-X PMID:
11312102
[40] Autiero, M.; Waltenberger, J.; Communi, D.; Kranz, A.; Moons,
L.; Lambrechts, D.; Kroll, J.; Plaisance, S.; De Mol, M.; Bono, F.;
Kliche, S.; Fellbrich, G.; Ballmer-Hofer, K.; Maglione, D.; Mayr-
Beyrle, U.; Dewerchin, M.; Dombrowski, S.; Stanimirovic, D.;
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 911
Van Hummelen, P.; Dehio, C.; Hicklin, D.J.; Persico, G.; Herbert,
J.M.; Communi, D.; Shibuya, M.; Collen, D.; Conway, E.M.;
Carmeliet, P. Role of PlGF in the intra- and intermolecular cross
talk between the VEGF receptors Flt1 and Flk1. Nat. Med., 2003,
9(7), 936-943.
http://dx.doi.org/10.1038/nm884 PMID: 12796773
[41] Jackson, M.W.; Roberts, J.S.; Heckford, S.E.; Ricciardelli, C.;
Stahl, J.; Choong, C.; Horsfall, D.J.; Tilley, W.D. A potential au-
tocrine role for vascular endothelial growth factor in prostate can-
cer. Cancer Res., 2002, 62(3), 854-859.
PMID: 11830543
[42] Frank, N.Y.; Schatton, T.; Kim, S.; Zhan, Q.; Wilson, B.J.; Ma, J.;
Saab, K.R.; Osherov, V.; Widlund, H.R.; Gasser, M.; Waaga-
Gasser, A.M.; Kupper, T.S.; Murphy, G.F.; Frank, M.H. VEGFR-
1 expressed by malignant melanoma-initiating cells is required for
tumor growth. Cancer Res., 2011, 71(4), 1474-1485.
http://dx.doi.org/10.1158/0008-5472.CAN-10-1660 PMID:
21212411
[43] Yang, A.D.; Camp, E.R.; Fan, F.; Shen, L.; Gray, M.J.; Liu, W.;
Somcio, R.; Bauer, T.W.; Wu, Y.; Hicklin, D.J.; Ellis, L.M. Vas-
cular endothelial growth factor receptor-1 activation mediates epi-
thelial to mesenchymal transition in human pancreatic carcinoma
cells. Cancer Res., 2006, 66(1), 46-51.
http://dx.doi.org/10.1158/0008-5472.CAN-05-3086 PMID:
16397214
[44] Fan, F.; Wey, J.S.; McCarty, M.F.; Belcheva, A.; Liu, W.; Bauer,
T.W.; Somcio, R.J.; Wu, Y.; Hooper, A.; Hicklin, D.J.; Ellis, L.M.
Expression and function of vascular endothelial growth factor re-
ceptor-1 on human colorectal cancer cells. Oncogene., 2005,
24(16), 2647-2653.
http://dx.doi.org/10.1038/sj.onc.1208246 PMID: 15735759
[45] D’Haene, N.; Koopmansch, C.; Van Eycke, Y-R.; Hulet, F.; Al-
lard, J.; Bouri, S.; Rorive, S.; Remmelink, M.; Decaestecker, C.;
Maris, C.; Salmon, I. The prognostic value of the combination of
low VEGFR-1 and High VEGFR-2 expression in endothelial cells
of colorectal cancer. Int. J. Mol. Sci., 2018, 19(11), 3536.
http://dx.doi.org/10.3390/ijms19113536 PMID: 30423986
[46] Vincent, L.; Jin, D.K.; Karajannis, M.A.; Shido, K.; Hooper, A.T.;
Rashbaum, W.K.; Pytowski, B.; Wu, Y.; Hicklin, D.J.; Zhu, Z.;
Bohlen, P.; Niesvizky, R.; Rafii, S. Fetal stromal-dependent para-
crine and intracrine vascular endothelial growth factor-a/vascular
endothelial growth factor receptor-1 signaling promotes prolifera-
tion and motility of human primary myeloma cells. Cancer Res.,
2005, 65(8), 3185-3192.
http://dx.doi.org/10.1158/0008-5472.CAN-04-3598 PMID:
15833849
[47] Ghosh, S.; Sullivan, C.A.; Zerkowski, M.P.; Molinaro, A.M.;
Rimm, D.L.; Camp, R.L.; Chung, G.G. High levels of vascular
endothelial growth factor and its receptors (VEGFR-1, VEGFR-2,
neuropilin-1) are associated with worse outcome in breast cancer.
Hum. Pathol., 2008, 39(12), 1835-1843.
http://dx.doi.org/10.1016/j.humpath.2008.06.004 PMID:
18715621
[48] Wu, Y.; Hooper, A.T.; Zhong, Z.; Witte, L.; Bohlen, P.; Rafii, S.;
Hicklin, D.J. The vascular endothelial growth factor receptor
(VEGFR-1) supports growth and survival of human breast carci-
noma. Int. J. Cancer., 2006, 119(7), 1519-1529.
http://dx.doi.org/10.1002/ijc.21865 PMID: 16671089
[49] Lampugnani, M.G.; Orsenigo, F.; Gagliani, M.C.; Tacchetti, C.;
Dejana, E. Vascular endothelial cadherin controls VEGFR-2 inter-
nalization and signaling from intracellular compartments. J. Cell
Biol., 2006, 174(4), 593-604.
http://dx.doi.org/10.1083/jcb.200602080 PMID: 16893970
[50] Takahashi, T.; Yamaguchi, S.; Chida, K.; Shibuya, M. A single
autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-
dependent activation of PLC-γ and DNA synthesis in vascular en-
dothelial cells. EMBO J., 2001, 20(11), 2768-2778.
http://dx.doi.org/10.1093/emboj/20.11.2768 PMID: 11387210
[51] Holmqvist, K.; Cross, M.J.; Rolny, C.; Hägerkvist, R.; Rahimi, N.;
Matsumoto, T.; Claesson-Welsh, L.; Welsh, M. The adaptor pro-
tein shb binds to tyrosine 1175 in vascular endothelial growth fac-
912 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
tor (VEGF) receptor-2 and regulates VEGF-dependent cellular
migration. J. Biol. Chem., 2004, 279(21), 22267-22275.
http://dx.doi.org/10.1074/jbc.M312729200 PMID: 15026417
[52] Yan, J-D.; Liu, Y.; Zhang, Z-Y.; Liu, G-Y.; Xu, J-H.; Liu, L-Y.;
Hu, Y.M. Expression and prognostic significance of VEGFR-2 in
breast cancer. Pathol. Res. Pract., 2015, 211(7), 539-543.
http://dx.doi.org/10.1016/j.prp.2015.04.003 PMID: 25976977
[53] Doi, Y.; Yashiro, M.; Yamada, N.; Amano, R.; Noda, S.; Hiraka-
wa, K. VEGF-A/VEGFR-2 signaling plays an important role for
the motility of pancreas cancer cells. Ann. Surg. Oncol., 2012,
19(8), 2733-2743.
http://dx.doi.org/10.1245/s10434-011-2181-6 PMID: 22207048
[54] Gille, J.; Heidenreich, R.; Pinter, A.; Schmitz, J.; Boehme, B.;
Hicklin, D.J.; Henschler, R.; Breier, G. Simultaneous blockade of
VEGFR-1 and VEGFR-2 activation is necessary to efficiently in-
hibit experimental melanoma growth and metastasis formation.
Int. J. Cancer., 2007, 120(9), 1899-1908.
http://dx.doi.org/10.1002/ijc.22531 PMID: 17230507
[55] Dias, S.; Hattori, K.; Zhu, Z.; Heissig, B.; Choy, M.; Lane, W.;
Wu, Y.; Chadburn, A.; Hyjek, E.; Gill, M.; Hicklin, D.J.; Witte,
L.; Moore, M.A.; Rafii, S. Autocrine stimulation of VEGFR-2 ac-
tivates human leukemic cell growth and migration. J. Clin. Invest.,
2000, 106(4), 511-521.
http://dx.doi.org/10.1172/JCI8978 PMID: 10953026
[56] Park, M.S.; Dong, S.M.; Kim, B-R.; Seo, S.H.; Kang, S.; Lee, E-
J.; Lee, S.H.; Rho, S.B. Thioridazine inhibits angiogenesis and
tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in
ovarian cancer xenografts. Oncotarget., 2014, 5(13), 4929-4934.
http://dx.doi.org/10.18632/oncotarget.2063 PMID: 24952635
[57] Tokuyama, W.; Mikami, T.; Masuzawa, M.; Okayasu, I. Autocrine
and paracrine roles of VEGF/VEGFR-2 and VEGF-C/VEGFR-3
signaling in angiosarcomas of the scalp and face. Hum. Pathol.,
2010, 41(3), 407-414.
http://dx.doi.org/10.1016/j.humpath.2009.08.021 PMID:
19913279
[58] Dixelius, J.; Makinen, T.; Wirzenius, M.; Karkkainen, M.J.;
Wernstedt, C.; Alitalo, K.; Claesson-Welsh, L. Ligand-induced
vascular endothelial growth factor receptor-3 (VEGFR-3) hetero-
dimerization with VEGFR-2 in primary lymphatic endothelial
cells regulates tyrosine phosphorylation sites. J. Biol. Chem.,
2003, 278(42), 40973-40979.
http://dx.doi.org/10.1074/jbc.M304499200 PMID: 12881528
[59] Mäkinen, T.; Veikkola, T.; Mustjoki, S.; Karpanen, T.; Catimel,
B.; Nice, E.C.; Wise, L.; Mercer, A.; Kowalski, H.; Kerjaschki,
D.; Stacker, S.A.; Achen, M.G.; Alitalo, K. Isolated lymphatic en-
dothelial cells transduce growth, survival and migratory signals via
the VEGF-C/D receptor VEGFR-3. EMBO J., 2001, 20(17), 4762-
4773.
http://dx.doi.org/10.1093/emboj/20.17.4762 PMID: 11532940
[60] Donnem, T.; Al-Saad, S.; Al-Shibli, K.; Busund, L-T.; Bremnes,
R.M. Co-expression of PDGF-B and VEGFR-3 strongly correlates
with lymph node metastasis and poor survival in non-small-cell
lung cancer. Ann. Oncol., 2010, 21(2), 223-231.
http://dx.doi.org/10.1093/annonc/mdp296 PMID: 19628565
[61] Valtola, R.; Salven, P.; Heikkilä, P.; Taipale, J.; Joensuu, H.;
Rehn, M.; Pihlajaniemi, T.; Weich, H.; deWaal, R.; Alitalo, K.
VEGFR-3 and its ligand VEGF-C are associated with angiogene-
sis in breast cancer. Am. J. Pathol., 1999, 154(5), 1381-1390.
http://dx.doi.org/10.1016/S0002-9440(10)65392-8 PMID:
10329591
[62] Van Trappen, PO; Steele, D; Lowe, DG; Baithun, S; Beasley, N;
Thiele, W Expression of vascular endothelial growth factor
(VEGF)‐C and VEGF‐D, and their receptor VEGFR‐3, during dif-
ferent stages of cervical carcinogenesis. J. Pathol., 2003, 201(4),
544-54.
[63] Jennbacken, K.; Vallbo, C.; Wang, W.; Damber, J.E. Expression
of vascular endothelial growth factor C (VEGF-C) and VEGF re-
ceptor-3 in human prostate cancer is associated with regional
lymph node metastasis. Prostate., 2005, 65(2), 110-116.
http://dx.doi.org/10.1002/pros.20276 PMID: 15880525
Malekan and Ebrahimzadeh
[64] Zhu, G.; Huang, Q.; Zheng, W.; Huang, Y.; Hua, J.; Yang, S.;
Zhuang, J.; Wang, J.; Chang, J.; Xu, J.; Ye, J. LPS upregulated
VEGFR-3 expression promote migration and invasion in colorec-
tal cancer via a mechanism of increased NF-κB binding to the
promoter of VEGFR-3. Cell. Physiol. Biochem., 2016, 39(5),
1665-1678.
http://dx.doi.org/10.1159/000447868 PMID: 27639612
[65] Madu, C.O.; Wang, S.; Madu, C.O.; Lu, Y. Angiogenesis in breast
cancer progression, diagnosis, and treatment. J. Cancer., 2020,
11(15), 4474-4494.
http://dx.doi.org/10.7150/jca.44313 PMID: 32489466
[66] Gimbrone, M.A., Jr; Gullino, P.M. Angiogenic capacity of prene-
oplastic lesions of the murine mammary gland as a marker of neo-
plastic transformation. Cancer Res., 1976, 36(7 PT 2), 2611-2620.
PMID: 1277168
[67] Arora, R.; Joshi, K.; Nijhawan, R.; Radotra, B.D.; Sharma, S.C.
Angiogenesis as an independent prognostic indicator in node-
negative breast cancer. Anal. Quant. Cytol. Histol., 2002, 24(4),
228-233.
PMID: 12199324
[68] Zhou, D.; Cheng, S-Q.; Ji, H-F.; Wang, J-S.; Xu, H-T.; Zhang, G-
Q.; Pang, D. Evaluation of protein pigment epithelium-derived
factor (PEDF) and microvessel density (MVD) as prognostic indi-
cators in breast cancer. J. Cancer Res. Clin. Oncol., 2010, 136(11),
1719-1727.
http://dx.doi.org/10.1007/s00432-010-0830-y PMID: 20229034
[69] Saponaro, C.; Malfettone, A.; Ranieri, G.; Danza, K.; Simone, G.;
Paradiso, A.; Mangia, A. VEGF, HIF-1α expression and MVD as
an angiogenic network in familial breast cancer. PLoS One., 2013,
8(1), e53070.
http://dx.doi.org/10.1371/journal.pone.0053070 PMID: 23326384
[70] Tsutsui, S.; Kume, M.; Era, S. Prognostic value of microvessel
density in invasive ductal carcinoma of the breast. Breast Cancer.,
2003, 10(4), 312-319.
http://dx.doi.org/10.1007/BF02967651 PMID: 14634509
[71] Choi, W.W.; Lewis, M.M.; Lawson, D.; Yin-Goen, Q.; Birdsong,
G.G.; Cotsonis, G.A.; Cohen, C.; Young, A.N. Angiogenic and
lymphangiogenic microvessel density in breast carcinoma: Corre-
lation with clinicopathologic parameters and VEGF-family gene
expression. Mod. Pathol., 2005, 18(1), 143-152.
http://dx.doi.org/10.1038/modpathol.3800253 PMID: 15297858
[72] Gasparini, G.; Barbareschi, M.; Boracchi, P.; Verderio, P.; Caffo,
O.; Meli, S.; Dalla Palma, P.; Marubini, E.; Bevilacqua, P. Tumor
angiogenesis predicts clinical outcome of node-positive breast
cancer patients treated with adjuvant hormone therapy or chemo-
therapy. Cancer J. Sci. Am., 1995, 1(2), 131-141.
PMID: 9166466
[73] Relf, M.; LeJeune, S.; Scott, P.A.; Fox, S.; Smith, K.; Leek, R.;
Moghaddam, A.; Whitehouse, R.; Bicknell, R.; Harris, A.L. Ex-
pression of the angiogenic factors vascular endothelial cell growth
factor, acidic and basic fibroblast growth factor, tumor growth fac-
tor β-1, platelet-derived endothelial cell growth factor, placenta
growth factor, and pleiotrophin in human primary breast cancer
and its relation to angiogenesis. Cancer Res., 1997, 57(5), 963-
969.
PMID: 9041202
[74] Ribatti, D.; Nico, B.; Ruggieri, S.; Tamma, R.; Simone, G.; Man-
gia, A. Angiogenesis and antiangiogenesis in triple-negative breast
cancer. Transl. Oncol., 2016, 9(5), 453-457.
http://dx.doi.org/10.1016/j.tranon.2016.07.002 PMID: 27751350
[75] Banerjee, S.; Dowsett, M.; Ashworth, A.; Martin, L-A. Mecha-
nisms of disease: Angiogenesis and the management of breast can-
cer. Nat. Clin. Pract. Oncol., 2007, 4(9), 536-550.
http://dx.doi.org/10.1038/ncponc0905 PMID: 17728712
[76] De Paola, F.; Granato, A.M.; Scarpi, E.; Monti, F.; Medri, L.;
Bianchi, S.; Amadori, D.; Volpi, A. Vascular endothelial growth
factor and prognosis in patients with node-negative breast cancer.
Int. J. Cancer., 2002, 98(2), 228-233.
http://dx.doi.org/10.1002/ijc.10118 PMID: 11857413
[77] Gasparini, G.; Toi, M.; Miceli, R.; Vermeulen, P.B.; Dittadi, R.;
Biganzoli, E.; Morabito, A.; Fanelli, M.; Gatti, C.; Suzuki, H.;
VEGFRs as a Target in Breast Cancer
Tominaga, T.; Dirix, L.Y.; Gion, M. Clinical relevance of vascular
endothelial growth factor and thymidine phosphorylase in patients
with node-positive breast cancer treated with either adjuvant
chemotherapy or hormone therapy. Cancer J. Sci. Am., 1999, 5(2),
101-111.
PMID: 10198732
[78] Foekens, J.A.; Peters, H.A.; Grebenchtchikov, N.; Look, M.P.;
Meijer-van Gelder, M.E.; Geurts-Moespot, A.; van der Kwast,
T.H.; Sweep, C.G.; Klijn, J.G. High tumor levels of vascular endo-
thelial growth factor predict poor response to systemic therapy in
advanced breast cancer. Cancer Res., 2001, 61(14), 5407-5414.
PMID: 11454684
[79] Schmidt, M.; Voelker, H-U.; Kapp, M.; Dietl, J.; Kammerer, U.
Expression of VEGFR-1 (Flt-1) in breast cancer is associated with
VEGF expression and with node-negative tumour stage. Anti-
cancer Res., 2008, 28(3A), 1719-1724.
PMID: 18630531
[80] Srabovic, N; Mujagic, Z; Mujanovic-Mustedanagic, J; Softic, A;
Muminovic, Z; Rifatbegovic, A Vascular endothelial growth factor
receptor-1 expression in breast cancer and its correlation to vascu-
lar endothelial growth factor a. Int J Breast Cancer., 2013, 2013
http://dx.doi.org/10.1155/2013/746749
[81] Ning, Q.; Liu, C.; Hou, L.; Meng, M.; Zhang, X.; Luo, M.; Shao,
S.; Zuo, X.; Zhao, X. Vascular endothelial growth factor receptor-
1 activation promotes migration and invasion of breast cancer cells
through epithelial-mesenchymal transition. PLoS One., 2013, 8(6),
e65217.
http://dx.doi.org/10.1371/journal.pone.0065217 PMID: 23776453
[82] Rydén, L.; Linderholm, B.; Nielsen, N.H.; Emdin, S.; Jönsson, P-
E.; Landberg, G. Tumor specific VEGF-A and VEGFR2/KDR
protein are co-expressed in breast cancer. Breast Cancer Res.
Treat., 2003, 82(3), 147-154.
http://dx.doi.org/10.1023/B:BREA.0000004357.92232.cb PMID:
14703061
[83] Raica, M.; Cimpean, A.M.; Ceausu, R.; Ribatti, D. Lymphatic
microvessel density, VEGF-C, and VEGFR-3 expression in differ-
ent molecular types of breast cancer. Anticancer Res., 2011, 31(5),
1757-1764.
PMID: 21617236
[84] van Iterson, V.; Leidenius, M.; von Smitten, K.; Bono, P.; Heik-
kilä, P. VEGF-D in association with VEGFR-3 promotes nodal
metastasis in human invasive lobular breast cancer. Am. J. Clin.
Pathol., 2007, 128(5), 759-766.
http://dx.doi.org/10.1309/7FXVRMXF58PVRJUH PMID:
17951197
[85] Levitzki, A.; Mishani, E. Tyrphostins and other tyrosine kinase
inhibitors. Annu. Rev. Biochem., 2006, 75(1), 93-109.
http://dx.doi.org/10.1146/annurev.biochem.75.103004.142657
PMID: 16756486
[86] Ivy, S.P.; Wick, J.Y.; Kaufman, B.M. An overview of small-
molecule inhibitors of VEGFR signaling. Nat. Rev. Clin. Oncol.,
2009, 6(10), 569-579.
http://dx.doi.org/10.1038/nrclinonc.2009.130 PMID: 19736552
[87] Yousefian, M.; Ghodsi, R. Structure-activity relationship studies
of indolin-2-one derivatives as vascular endothelial growth factor
receptor inhibitors and anticancer agents. Arch. Pharm. (Wein-
heim)., 2020, 353(12), e2000022.
http://dx.doi.org/10.1002/ardp.202000022 PMID: 32885522
[88] O’Farrell, A-M.; Abrams, T.J.; Yuen, H.A.; Ngai, T.J.; Louie,
S.G.; Yee, K.W.; Wong, L.M.; Hong, W.; Lee, L.B.; Town, A.;
Smolich, B.D.; Manning, W.C.; Murray, L.J.; Heinrich, M.C.;
Cherrington, J.M. SU11248 is a novel FLT3 tyrosine kinase inhib-
itor with potent activity in vitro and in vivo. Blood., 2003, 101(9),
3597-3605.
http://dx.doi.org/10.1182/blood-2002-07-2307 PMID: 12531805
[89] Safe, S.; Kasiappan, R. Natural products as mechanism-based
anticancer agents: Sp transcription factors as targets. Phytother.
Res., 2016, 30(11), 1723-1732.
http://dx.doi.org/10.1002/ptr.5669 PMID: 27384261
[90] Shimizu, M.; Shirakami, Y.; Sakai, H.; Yasuda, Y.; Kubota, M.;
Adachi, S.; Tsurumi, H.; Hara, Y.; Moriwaki, H. (-)-
Epigallocatechin gallate inhibits growth and activation of the
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 913
VEGF/VEGFR axis in human colorectal cancer cells. Chem. Biol.
Interact., 2010, 185(3), 247-252.
http://dx.doi.org/10.1016/j.cbi.2010.03.036 PMID: 20346928
[91] Garvin, S.; Ollinger, K.; Dabrosin, C. Resveratrol induces apopto-
sis and inhibits angiogenesis in human breast cancer xenografts in
vivo. Cancer Lett., 2006, 231(1), 113-122.
http://dx.doi.org/10.1016/j.canlet.2005.01.031 PMID: 16356836
[92] Fan, S.; Xu, Y.; Li, X.; Tie, L.; Pan, Y.; Li, X. Opposite angiogen-
ic outcome of curcumin against ischemia and Lewis lung cancer
models: In silico , in vitro and in vivo studies. Biochim. Biophys.
Acta., 2014, 1842(9), 1742-1754.
http://dx.doi.org/10.1016/j.bbadis.2014.06.019 PMID: 24970744
[93] Lu, N.; Gao, Y.; Ling, Y.; Chen, Y.; Yang, Y.; Gu, H.Y.; Qi, Q.;
Liu, W.; Wang, X.T.; You, Q.D.; Guo, Q.L. Wogonin suppresses
tumor growth in vivo and VEGF-induced angiogenesis through in-
hibiting tyrosine phosphorylation of VEGFR2. Life Sci., 2008,
82(17-18), 956-963.
http://dx.doi.org/10.1016/j.lfs.2008.02.013 PMID: 18378261
[94] He, M.F.; Huang, Y.H.; Wu, L.W.; Ge, W.; Shaw, P.C.; But, P.P.
Triptolide functions as a potent angiogenesis inhibitor. Int. J. Can-
cer., 2010, 126(1), 266-278.
http://dx.doi.org/10.1002/ijc.24694 PMID: 19569053
[95] Hasanzadeh, D.; Mahdavi, M.; Dehghan, G.; Charoudeh, H.N.
Farnesiferol C induces cell cycle arrest and apoptosis mediated by
oxidative stress in MCF-7 cell line. Toxicol. Rep., 2017, 4, 420-
426.
http://dx.doi.org/10.1016/j.toxrep.2017.07.010 PMID: 28959668
[96] Hong, O.Y.; Noh, E.M.; Jang, H.Y.; Lee, Y.R.; Lee, B.K.; Jung,
S.H.; Kim, J.S.; Youn, H.J. Epigallocatechin gallate inhibits the
growth of MDA-MB-231 breast cancer cells via inactivation of the
β-catenin signaling pathway. Oncol. Lett., 2017, 14(1), 441-446.
http://dx.doi.org/10.3892/ol.2017.6108 PMID: 28693189
[97] Luo, T.; Wang, J.; Yin, Y.; Hua, H.; Jing, J.; Sun, X.; Li, M.;
Zhang, Y.; Jiang, Y. (-)-Epigallocatechin gallate sensitizes breast
cancer cells to paclitaxel in a murine model of breast carcinoma.
Breast Cancer Res., 2010, 12(1), R8.
http://dx.doi.org/10.1186/bcr2473 PMID: 20078855
[98] Zan, L.; Chen, Q.; Zhang, L.; Li, X. Epigallocatechin gallate
(EGCG) suppresses growth and tumorigenicity in breast cancer
cells by downregulation of miR-25. Bioengineered., 2019, 10(1),
374-382.
http://dx.doi.org/10.1080/21655979.2019.1657327 PMID:
31431131
[99] Al-Ani, B. Resveratrol inhibits proteinase-activated receptor-2-
induced release of soluble vascular endothelial growth factor re-
ceptor-1 from human endothelial cells. EXCLI J., 2013, 12, 598-
604.
PMID: 26933402
[100] Tang, F.Y.; Su, Y.C.; Chen, N.C.; Hsieh, H.S.; Chen, K.S.
Resveratrol inhibits migration and invasion of human breast-
cancer cells. Mol. Nutr. Food Res., 2008, 52(6), 683-691.
http://dx.doi.org/10.1002/mnfr.200700325 PMID: 18398872
[101] Leon-Galicia, I.; Diaz-Chavez, J.; Albino-Sanchez, M.E.; Garcia-
Villa, E.; Bermudez-Cruz, R.; Garcia-Mena, J.; Herrera, L.A.;
García-Carrancá, A.; Gariglio, P. Resveratrol decreases Rad51 ex-
pression and sensitizes cisplatin-resistant MCF-7 breast cancer
cells. Oncol. Rep., 2018, 39(6), 3025-3033.
http://dx.doi.org/10.3892/or.2018.6336 PMID: 29620223
[102] Zhu, W.; Qin, W.; Zhang, K.; Rottinghaus, G.E.; Chen, Y.C.;
Kliethermes, B.; Sauter, E.R. Trans-resveratrol alters mammary
promoter hypermethylation in women at increased risk for breast
cancer. Nutr. Cancer., 2012, 64(3), 393-400.
http://dx.doi.org/10.1080/01635581.2012.654926 PMID:
22332908
[103] Hu, C.; Li, M.; Guo, T.; Wang, S.; Huang, W.; Yang, K.; Liao, Z.;
Wang, J.; Zhang, F.; Wang, H. Anti-metastasis activity of curcu-
min against breast cancer via the inhibition of stem cell-like prop-
erties and EMT. Phytomedicine., 2019, 58, 152740.
http://dx.doi.org/10.1016/j.phymed.2018.11.001 PMID: 31005718
[104] Li, M.; Lin, L.; Guo, T.; Wu, Y.; Lin, J.; Liu, Y.; Yang, K.; Hu, C.
Curcumin administered in combination with Glu-GNPs induces
914 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
radiosensitivity in transplanted tumor MDA-MB-231-luc cells in
nude mice. BioMed Res. Int., 2021, 2021, 9262453.
http://dx.doi.org/10.1155/2021/9262453 PMID: 34825004
[105] Zhou, S.; Li, J.; Xu, H.; Zhang, S.; Chen, X.; Chen, W.; Yang, S.;
Zhong, S.; Zhao, J.; Tang, J. Liposomal curcumin alters chemo-
sensitivity of breast cancer cells to Adriamycin via regulating mi-
croRNA expression. Gene., 2017, 622, 1-12.
http://dx.doi.org/10.1016/j.gene.2017.04.026 PMID: 28431975
[106] Saghatelyan, T.; Tananyan, A.; Janoyan, N.; Tadevosyan, A.;
Petrosyan, H.; Hovhannisyan, A.; Hayrapetyan, L.; Arustamyan,
M.; Arnhold, J.; Rotmann, A.R.; Hovhannisyan, A.; Panossian, A.
Efficacy and safety of curcumin in combination with paclitaxel in
patients with advanced, metastatic breast cancer: A comparative,
randomized, double-blind, placebo-controlled clinical trial. Phy-
tomedicine., 2020, 70, 153218.
http://dx.doi.org/10.1016/j.phymed.2020.153218 PMID: 32335356
[107] Chung, H.; Jung, Y.M.; Shin, D.H.; Lee, J.Y.; Oh, M.Y.; Kim,
H.J.; Jang, K.S.; Jeon, S.J.; Son, K.H.; Kong, G. Anticancer ef-
fects of wogonin in both estrogen receptor-positive and -negative
human breast cancer cell lines in vitro and in nude mice xeno-
grafts. Int. J. Cancer., 2008, 122(4), 816-822.
http://dx.doi.org/10.1002/ijc.23182 PMID: 17957784
[108] Huang, K.F.; Zhang, G.D.; Huang, Y.Q.; Diao, Y. Wogonin in-
duces apoptosis and down-regulates survivin in human breast can-
cer MCF-7 cells by modulating PI3K-AKT pathway. Int. Im-
munopharmacol., 2012, 12(2), 334-341.
http://dx.doi.org/10.1016/j.intimp.2011.12.004 PMID: 22182776
[109] Tang, Y.; Wang, J.; Cheng, J.; Wang, L. Antiestrogenic activity of
triptolide in human breast cancer cells MCF-7 and immature fe-
male mouse. Drug Dev. Res., 2017, 78(3-4), 164-169.
http://dx.doi.org/10.1002/ddr.21387 PMID: 28608490
[110] Varghese, E.; Samuel, S.M.; Varghese, S.; Cheema, S.; Mamtani,
R.; Büsselberg, D. Triptolide decreases cell proliferation and in-
duces cell death in triple negative MDA-MB-231 breast cancer
cells. Biomolecules., 2018, 8(4), E163.
http://dx.doi.org/10.3390/biom8040163 PMID: 30563138
[111] Shi, J.; Li, J.; Li, J.; Li, R.; Wu, X.; Gao, F.; Zou, L.; Mak,
W.W.S.; Fu, C.; Zhang, J.; Leung, G.P. Synergistic breast cancer
suppression efficacy of doxorubicin by combination with glycyr-
rhetinic acid as an angiogenesis inhibitor. Phytomedicine., 2021,
81, 153408.
http://dx.doi.org/10.1016/j.phymed.2020.153408 PMID: 33234363
[112] Rahimi, N. Vascular endothelial growth factor receptors: Molecu-
lar mechanisms of activation and therapeutic potentials. Exp. Eye
Res., 2006, 83(5), 1005-1016.
http://dx.doi.org/10.1016/j.exer.2006.03.019 PMID: 16713597
[113] Harris, P.A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R.M.;
Davis-Ward, R.G.; Epperly, A.H.; Hinkle, K.W.; Hunter, R.N., III;
Johnson, J.H.; Knick, V.B.; Laudeman, C.P.; Luttrell, D.K.;
Mook, R.A.; Nolte, R.T.; Rudolph, S.K.; Szewczyk, J.R.; Trues-
dale, A.T.; Veal, J.M.; Wang, L.; Stafford, J.A. Discovery of 5-
[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-
pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a
novel and potent vascular endothelial growth factor receptor inhib-
itor. J. Med. Chem., 2008, 51(15), 4632-4640.
http://dx.doi.org/10.1021/jm800566m PMID: 18620382
[114] Hosaka, S.; Horiuchi, K.; Yoda, M.; Nakayama, R.; Tohmonda,
T.; Susa, M.; Nakamura, M.; Chiba, K.; Toyama, Y.; Morioka, H.
A novel multi-kinase inhibitor pazopanib suppresses growth of
synovial sarcoma cells through inhibition of the PI3K-AKT path-
way. J. Orthop. Res., 2012, 30(9), 1493-1498.
http://dx.doi.org/10.1002/jor.22091 PMID: 22359392
[115] Kernt, M.; Thiele, S.; Neubauer, A.S.; Koenig, S.; Hirneiss, C.;
Haritoglou, C.; Ulbig, M.W.; Kampik, A. Inhibitory activity of
ranibizumab, sorafenib, and pazopanib on light-induced overex-
pression of platelet-derived growth factor and vascular endothelial
growth factor A and the vascular endothelial growth factor A re-
ceptors 1 and 2 and neuropilin 1 and 2. Retina., 2012, 32(8), 1652-
1663.
http://dx.doi.org/10.1097/IAE.0b013e318240a558 PMID:
22466477
Malekan and Ebrahimzadeh
[116] Taylor, S.K.; Chia, S.; Dent, S.; Clemons, M.; Agulnik, M.;
Grenci, P.; Wang, L.; Oza, A.M.; Ivy, P.; Pritchard, K.I.; Leighl,
N.B. A phase II study of pazopanib in patients with recurrent or
metastatic invasive breast carcinoma: A trial of the Princess Mar-
garet Hospital phase II consortium. Oncologist., 2010, 15(8), 810-
818.
http://dx.doi.org/10.1634/theoncologist.2010-0081 PMID:
20682606
[117] Johnston, S.R.; Gómez, H.; Stemmer, S.M.; Richie, M.; Durante,
M.; Pandite, L.; Goodman, V.; Slamon, D. A randomized and
open-label trial evaluating the addition of pazopanib to lapatinib as
first-line therapy in patients with HER2-positive advanced breast
cancer. Breast Cancer Res. Treat., 2013, 137(3), 755-766.
http://dx.doi.org/10.1007/s10549-012-2399-4 PMID: 23283526
[118] Cristofanilli, M.; Johnston, S.R.; Manikhas, A.; Gomez, H.L.;
Gladkov, O.; Shao, Z.; Safina, S.; Blackwell, K.L.; Alvarez, R.H.;
Rubin, S.D.; Ranganathan, S.; Redhu, S.; Trudeau, M.E. A ran-
domized phase II study of lapatinib + pazopanib versus lapatinib
in patients with HER2+ inflammatory breast cancer. Breast Cancer
Res. Treat., 2013, 137(2), 471-482.
http://dx.doi.org/10.1007/s10549-012-2369-x PMID: 23239151
[119] Tan, A.R.; Johannes, H.; Rastogi, P.; Jacobs, S.A.; Robidoux, A.;
Flynn, P.J.; Thirlwell, M.P.; Fehrenbacher, L.; Stella, P.J.; Goel,
R.; Julian, T.B.; Provencher, L.; Bury, M.J.; Bhatt, K.; Geyer,
C.E., Jr; Swain, S.M.; Mamounas, E.P.; Wolmark, N. Weekly
paclitaxel and concurrent pazopanib following doxorubicin and
cyclophosphamide as neoadjuvant therapy for HER-negative lo-
cally advanced breast cancer: NSABP Foundation FB-6, a phase II
study. Breast Cancer Res. Treat., 2015, 149(1), 163-169.
http://dx.doi.org/10.1007/s10549-014-3221-2 PMID: 25542269
[120] Wedge, S.R.; Kendrew, J.; Hennequin, L.F.; Valentine, P.J.; Bar-
ry, S.T.; Brave, S.R.; Smith, N.R.; James, N.H.; Dukes, M.; Cur-
wen, J.O.; Chester, R.; Jackson, J.A.; Boffey, S.J.; Kilburn, L.L.;
Barnett, S.; Richmond, G.H.; Wadsworth, P.F.; Walker, M.;
Bigley, A.L.; Taylor, S.T.; Cooper, L.; Beck, S.; Jürgensmeier,
J.M.; Ogilvie, D.J. AZD2171: A highly potent, orally bioavailable,
vascular endothelial growth factor receptor-2 tyrosine kinase in-
hibitor for the treatment of cancer. Cancer Res., 2005, 65(10),
4389-4400.
http://dx.doi.org/10.1158/0008-5472.CAN-04-4409 PMID:
15899831
[121] Ivy, S.P.; Liu, J.F.; Lee, J-M.; Matulonis, U.A.; Kohn, E.C.
Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibi-
tor, in combination therapy for high grade serous ovarian cancer.
Expert Opin. Investig. Drugs., 2016, 25(5), 597-611.
http://dx.doi.org/10.1517/13543784.2016.1156857 PMID:
26899229
[122] Morton, C.L.; Maris, J.M.; Keir, S.T.; Gorlick, R.; Kolb, E.A.;
Billups, C.A.; Wu, J.; Smith, M.A.; Houghton, P.J. Combination
testing of cediranib (AZD2171) against childhood cancer models
by the pediatric preclinical testing program. Pediatr. Blood Can-
cer., 2012, 58(4), 566-571.
http://dx.doi.org/10.1002/pbc.23159 PMID: 21538824
[123] Liu, J.F.; Tolaney, S.M.; Birrer, M.; Fleming, G.F.; Buss, M.K.;
Dahlberg, S.E.; Lee, H.; Whalen, C.; Tyburski, K.; Winer, E.; Ivy,
P.; Matulonis, U.A. A Phase 1 trial of the poly(ADP-ribose) poly-
merase inhibitor olaparib (AZD2281) in combination with the an-
ti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian
or triple-negative breast cancer. Eur. J. Cancer., 2013, 49(14),
2972-2978.
http://dx.doi.org/10.1016/j.ejca.2013.05.020 PMID: 23810467
[124] Hong, D.S.; Garrido-Laguna, I.; Ekmekcioglu, S.; Falchook, G.S.;
Naing, A.; Wheler, J.J.; Fu, S.; Moulder, S.L.; Piha-Paul, S.;
Tsimberidou, A.M.; Wen, Y.; Culotta, K.S.; Anderes, K.; Davis,
D.W.; Liu, W.; George, G.C.; Camacho, L.H.; Percy Ivy, S.; Kur-
zrock, R. Dual inhibition of the vascular endothelial growth factor
pathway: A phase 1 trial evaluating bevacizumab and AZD2171
(cediranib) in patients with advanced solid tumors. Cancer., 2014,
120(14), 2164-2173.
http://dx.doi.org/10.1002/cncr.28701 PMID: 24752867
VEGFRs as a Target in Breast Cancer
[125] Hyams, D.M.; Chan, A.; de Oliveira, C.; Snyder, R.; Vinholes, J.;
Audeh, M.W.; Alencar, V.M.; Lombard, J.; Mookerjee, B.; Xu, J.;
Brown, K.; Klein, P. Cediranib in combination with fulvestrant in
hormone-sensitive metastatic breast cancer: A randomized phase II
study. Invest. New Drugs., 2013, 31(5), 1345-1354.
http://dx.doi.org/10.1007/s10637-013-9991-2 PMID: 23801303
[126] Trudel, S.; Li, Z.H.; Wei, E.; Wiesmann, M.; Chang, H.; Chen, C.;
Reece, D.; Heise, C.; Stewart, A.K. CHIR-258, a novel, multitar-
geted tyrosine kinase inhibitor for the potential treatment of t(4;14)
multiple myeloma. Blood., 2005, 105(7), 2941-2948.
http://dx.doi.org/10.1182/blood-2004-10-3913 PMID: 15598814
[127] Lee, S.H.; Lopes de Menezes, D.; Vora, J.; Harris, A.; Ye, H.;
Nordahl, L.; Garrett, E.; Samara, E.; Aukerman, S.L.; Gelb, A.B.;
Heise, C. In vivo target modulation and biological activity of
CHIR-258, a multitargeted growth factor receptor kinase inhibitor,
in colon cancer models. Clin. Cancer Res., 2005, 11(10), 3633-
3641.
http://dx.doi.org/10.1158/1078-0432.CCR-04-2129 PMID:
15897558
[128] Huynh, H.; Chow, P.K.H.; Tai, W.M.; Choo, S.P.; Chung, A.Y.F.;
Ong, H.S.; Soo, K.C.; Ong, R.; Linnartz, R.; Shi, M.M. Dovitinib
demonstrates antitumor and antimetastatic activities in xenograft
models of hepatocellular carcinoma. J. Hepatol., 2012, 56(3), 595-
601.
http://dx.doi.org/10.1016/j.jhep.2011.09.017 PMID: 22027573
[129] André, F.; Bachelot, T.; Campone, M.; Dalenc, F.; Perez-Garcia,
J.M.; Hurvitz, S.A.; Turner, N.; Rugo, H.; Smith, J.W.; Deudon,
S.; Shi, M.; Zhang, Y.; Kay, A.; Porta, D.G.; Yovine, A.; Baselga,
J. Targeting FGFR with dovitinib (TKI258): Preclinical and clini-
cal data in breast cancer. Clin. Cancer Res., 2013, 19(13), 3693-
3702.
http://dx.doi.org/10.1158/1078-0432.CCR-13-0190 PMID:
23658459
[130] Musolino, A.; Campone, M.; Neven, P.; Denduluri, N.; Barrios,
C.H.; Cortes, J.; Blackwell, K.; Soliman, H.; Kahan, Z.; Bonnefoi,
H.; Squires, M.; Zhang, Y.; Deudon, S.; Shi, M.M.; André, F.
Phase II, randomized, placebo-controlled study of dovitinib in
combination with fulvestrant in postmenopausal patients with
HR+, HER2- breast cancer that had progressed during or after prior
endocrine therapy. Breast Cancer Res., 2017, 19(1), 18.
http://dx.doi.org/10.1186/s13058-017-0807-8 PMID: 28183331
[131] Roth, G.J.; Heckel, A.; Colbatzky, F.; Handschuh, S.; Kley, J.;
Lehmann-Lintz, T.; Lotz, R.; Tontsch-Grunt, U.; Walter, R.; Hil-
berg, F. Design, synthesis, and evaluation of indolinones as triple
angiokinase inhibitors and the discovery of a highly specific 6-
methoxycarbonyl-substituted indolinone (BIBF 1120). J. Med.
Chem., 2009, 52(14), 4466-4480.
http://dx.doi.org/10.1021/jm900431g PMID: 19522465
[132] Liu, C-Y.; Huang, T-T.; Chu, P-Y.; Huang, C-T.; Lee, C-H.;
Wang, W-L. The tyrosine kinase inhibitor nintedanib activates
SHP-1 and induces apoptosis in triple-negative breast cancer cells.
Exp. Mol. Med., 2017, 49(8), e366.
[133] Hilberg, F.; Tontsch-Grunt, U.; Baum, A.; Le, A.T.; Doebele,
R.C.; Lieb, S.; Gianni, D.; Voss, T.; Garin-Chesa, P.; Haslinger,
C.; Kraut, N. Triple angiokinase inhibitor nintedanib directly in-
hibits tumor cell growth and induces tumor shrinkagevia blocking
oncogenic receptor tyrosine kinases. J. Pharmacol. Exp. Ther.,
2018, 364(3), 494-503.
http://dx.doi.org/10.1124/jpet.117.244129 PMID: 29263244
[134] Reguera-Nuñez, E.; Xu, P.; Chow, A.; Man, S.; Hilberg, F.; Ker-
bel, R.S. Therapeutic impact of Nintedanib with paclitaxel and/or
a PD-L1 antibody in preclinical models of orthotopic primary or
metastatic triple negative breast cancer. J. Exp. Clin. Cancer Res.,
2019, 38(1), 16.
http://dx.doi.org/10.1186/s13046-018-0999-5 PMID: 30635009
[135] Quintela-Fandino, M.; Urruticoechea, A.; Guerra, J.; Gil, M.;
Gonzalez-Martin, A.; Marquez, R.; Hernandez-Agudo, E.; Rodri-
guez-Martin, C.; Gil-Martin, M.; Bratos, R.; Escudero, M.J.;
Vlassak, S.; Hilberg, F.; Colomer, R. Phase I clinical trial of
nintedanib plus paclitaxel in early HER-2-negative breast cancer
(CNIO-BR-01-2010/GEICAM-2010-10 study). Br. J. Cancer.,
2014, 111(6), 1060-1064.
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 915
http://dx.doi.org/10.1038/bjc.2014.397 PMID: 25058346
[136] Quintela-Fandino, M.; Apala, J.V.; Malon, D.; Mouron, S.;
Hornedo, J.; Gonzalez-Cortijo, L.; Colomer, R.; Guerra, J.
Nintedanib plus letrozole in early breast cancer: A phase 0/I phar-
macodynamic, pharmacokinetic, and safety clinical trial of com-
bined FGFR1 and aromatase inhibition. Breast Cancer Res., 2019,
21(1), 69.
http://dx.doi.org/10.1186/s13058-019-1152-x PMID: 31126332
[137] Quintela-Fandino, M.; Lluch, A.; Manso, L.; Calvo, I.; Cortes, J.;
García-Saenz, J.A.; Gil-Gil, M.; Martinez-Jánez, N.; Gonzalez-
Martin, A.; Adrover, E.; de Andres, R.; Viñas, G.; Llombart-
Cussac, A.; Alba, E.; Guerra, J.; Bermejo, B.; Zamora, E.; More-
no-Anton, F.; Pernas Simon, S.; Carrato, A.; Lopez-Alonso, A.;
Escudero, M.J.; Campo, R.; Carrasco, E.; Palacios, J.; Mulero, F.;
Colomer, R. 18F-fluoromisonidazole PET and activity of neoadju-
vant nintedanib in early HER2-negative breast cancer: A window-
of-opportunity randomized trial. Clin. Cancer Res., 2017, 23(6),
1432-1441.
http://dx.doi.org/10.1158/1078-0432.CCR-16-0738 PMID:
27587436
[138] Hu-Lowe, D.D.; Zou, H.Y.; Grazzini, M.L.; Hallin, M.E.; Wick-
man, G.R.; Amundson, K.; Chen, J.H.; Rewolinski, D.A.; Yama-
zaki, S.; Wu, E.Y.; McTigue, M.A.; Murray, B.W.; Kania, R.S.;
O’Connor, P.; Shalinsky, D.R.; Bender, S.L. Nonclinical antiangi-
ogenesis and antitumor activities of axitinib (AG-013736), an oral,
potent, and selective inhibitor of vascular endothelial growth fac-
tor receptor tyrosine kinases 1, 2, 3. Clin. Cancer Res., 2008,
14(22), 7272-7283.
http://dx.doi.org/10.1158/1078-0432.CCR-08-0652 PMID:
19010843
[139] Wilmes, L.J.; Pallavicini, M.G.; Fleming, L.M.; Gibbs, J.; Wang,
D.; Li, K-L.; Partridge, S.C.; Henry, R.G.; Shalinsky, D.R.; Hu-
Lowe, D.; Park, J.W.; McShane, T.M.; Lu, Y.; Brasch, R.C.;
Hylton, N.M. AG-013736, a novel inhibitor of VEGF receptor ty-
rosine kinases, inhibits breast cancer growth and decreases vascu-
lar permeability as detected by dynamic contrast-enhanced mag-
netic resonance imaging. Magn. Reson. Imaging., 2007, 25(3),
319-327.
http://dx.doi.org/10.1016/j.mri.2006.09.041 PMID: 17371720
[140] Verbeek, H.H.; Alves, M.M.; de Groot, J-W.B.; Osinga, J.; Pluk-
ker, J.T.; Links, T.P.; Hofstra, R.M. The effects of four different
tyrosine kinase inhibitors on medullary and papillary thyroid can-
cer cells. J. Clin. Endocrinol. Metab., 2011, 96(6), E991-E995.
http://dx.doi.org/10.1210/jc.2010-2381 PMID: 21470995
[141] Rössler, J.; Monnet, Y.; Farace, F.; Opolon, P.; Daudigeos-Dubus,
E.; Bourredjem, A.; Vassal, G.; Geoerger, B. The selective
VEGFR1-3 inhibitor axitinib (AG-013736) shows antitumor activ-
ity in human neuroblastoma xenografts. Int. J. Cancer., 2011,
128(11), 2748-2758.
http://dx.doi.org/10.1002/ijc.25611 PMID: 20715103
[142] Ma, Y.H.; Wang, S.Y.; Ren, Y.P.; Li, J.; Guo, T.J.; Lu, W.; Zhou,
T.Y. Antitumor effect of axitinib combined with dopamine and
PK-PD modeling in the treatment of human breast cancer xeno-
graft. Acta Pharmacol. Sin., 2019, 40(2), 243-256.
http://dx.doi.org/10.1038/s41401-018-0006-x PMID: 29773888
[143] Rugo, H.S.; Stopeck, A.T.; Joy, A.A.; Chan, S.; Verma, S.; Lluch,
A.; Liau, K.F.; Kim, S.; Bycott, P.; Rosbrook, B.; Bair, A.H.;
Soulieres, D. Randomized, placebo-controlled, double-blind,
phase II study of axitinib plus docetaxel versus docetaxel plus pla-
cebo in patients with metastatic breast cancer. J. Clin. Oncol.,
2011, 29(18), 2459-2465.
http://dx.doi.org/10.1200/JCO.2010.31.2975 PMID: 21555686
[144] Polverino, A.; Coxon, A.; Starnes, C.; Diaz, Z.; DeMelfi, T.;
Wang, L.; Bready, J.; Estrada, J.; Cattley, R.; Kaufman, S.; Chen,
D.; Gan, Y.; Kumar, G.; Meyer, J.; Neervannan, S.; Alva, G.; Tal-
venheimo, J.; Montestruque, S.; Tasker, A.; Patel, V.; Radinsky,
R.; Kendall, R. AMG 706, an oral, multikinase inhibitor that selec-
tively targets vascular endothelial growth factor, platelet-derived
growth factor, and kit receptors, potently inhibits angiogenesis and
induces regression in tumor xenografts. Cancer Res., 2006, 66(17),
8715-8721.
916 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
http://dx.doi.org/10.1158/0008-5472.CAN-05-4665 PMID:
16951187
[145] Coxon, A.; Ziegler, B.; Kaufman, S.; Xu, M.; Wang, H.;
Weishuhn, D.; Schmidt, J.; Sweet, H.; Starnes, C.; Saffran, D.;
Polverino, A. Antitumor activity of motesanib alone and in com-
bination with cisplatin or docetaxel in multiple human non-small-
cell lung cancer xenograft models. Mol. Cancer., 2012, 11(1), 70.
http://dx.doi.org/10.1186/1476-4598-11-70 PMID: 22992329
[146] Kaya, T.T.; Altun, A.; Turgut, N.H.; Ataseven, H.; Koyluoglu, G.
Effects of a multikinase inhibitor motesanib (AMG 706) alone and
combined with the selective DuP-697 COX-2 inhibitor on colorec-
tal cancer cells. Asian Pac. J. Cancer Prev., 2016, 17(3), 1103-
1110.
http://dx.doi.org/10.7314/APJCP.2016.17.3.1103 PMID:
27039732
[147] De Boer, R.H.; Kotasek, D.; White, S.; Koczwara, B.; Mainwar-
ing, P.; Chan, A.; Melara, R.; Ye, Y.; Adewoye, A.H.; Sikorski,
R.; Kaufman, P.A. Phase 1b dose-finding study of motesanib with
docetaxel or paclitaxel in patients with metastatic breast cancer.
Breast Cancer Res. Treat., 2012, 135(1), 241-252.
http://dx.doi.org/10.1007/s10549-012-2135-0 PMID: 22872523
[148] Martin, M.; Roche, H.; Pinter, T.; Crown, J.; Kennedy, M.J.; Pro-
vencher, L.; Priou, F.; Eiermann, W.; Adrover, E.; Lang, I.; Ra-
mos, M.; Latreille, J.; Jagiełło-Gruszfeld, A.; Pienkowski, T.; Al-
ba, E.; Snyder, R.; Almel, S.; Rolski, J.; Munoz, M.; Moroose, R.;
Hurvitz, S.; Baños, A.; Adewoye, H.; Hei, Y.J.; Lindsay, M.A.;
Rupin, M.; Cabaribere, D.; Lemmerick, Y.; Mackey, J.R.
Motesanib, or open-label bevacizumab, in combination with
paclitaxel, as first-line treatment for HER2-negative locally recur-
rent or metastatic breast cancer: A phase 2, randomised, double-
blind, placebo-controlled study. Lancet Oncol., 2011, 12(4), 369-
376.
http://dx.doi.org/10.1016/S1470-2045(11)70037-7 PMID:
21429799
[149] Nakamura, K.; Taguchi, E.; Miura, T.; Yamamoto, A.; Takahashi,
K.; Bichat, F.; Guilbaud, N.; Hasegawa, K.; Kubo, K.; Fujiwara,
Y.; Suzuki, R.; Kubo, K.; Shibuya, M.; Isae, T. KRN951, a highly
potent inhibitor of vascular endothelial growth factor receptor ty-
rosine kinases, has antitumor activities and affects functional vas-
cular properties. Cancer Res., 2006, 66(18), 9134-9142.
http://dx.doi.org/10.1158/0008-5472.CAN-05-4290 PMID:
16982756
[150] Taguchi, E.; Nakamura, K.; Miura, T.; Shibuya, M.; Isoe, T. Anti-
tumor activity and tumor vessel normalization by the vascular en-
dothelial growth factor receptor tyrosine kinase inhibitor KRN951
in a rat peritoneal disseminated tumor model. Cancer Sci., 2008,
99(3), 623-630.
http://dx.doi.org/10.1111/j.1349-7006.2007.00724.x PMID:
18201272
[151] Mayer, E.L.; Scheulen, M.E.; Beckman, J.; Richly, H.; Duarte, A.;
Cotreau, M.M.; Strahs, A.L.; Agarwal, S.; Steelman, L.; Winer,
E.P.; Dickler, M.N. A Phase I dose-escalation study of the
VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel
in metastatic breast cancer. Breast Cancer Res. Treat., 2013,
140(2), 331-339.
http://dx.doi.org/10.1007/s10549-013-2632-9 PMID: 23868188
[152] Mehta, M.; Griffith, J.; Panneerselvam, J.; Babu, A.; Mani, J.;
Herman, T. Regorafenib sensitizes human breast cancer cells to
radiation by inhibiting multiple kinases and inducing DNA dam-
age. Int. J. Radiat. Biol., 2021, 97(8), 1109-1120.
PMID: 32052681
[153] Matsui, J.; Funahashi, Y.; Uenaka, T.; Watanabe, T.; Tsuruoka,
A.; Asada, M. Multi-kinase inhibitor E7080 suppresses lymph
node and lung metastases of human mammary breast tumor MDA-
MB-231 via inhibition of vascular endothelial growth factor-
receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin. Cancer Res.,
2008, 14(17), 5459-5465.
http://dx.doi.org/10.1158/1078-0432.CCR-07-5270 PMID:
18765537
[154] Wilhelm, S.M.; Dumas, J.; Adnane, L.; Lynch, M.; Carter, C.A.;
Schütz, G.; Thierauch, K.H.; Zopf, D. Regorafenib (BAY 73-
Malekan and Ebrahimzadeh
4506): A new oral multikinase inhibitor of angiogenic, stromal and
oncogenic receptor tyrosine kinases with potent preclinical anti-
tumor activity. Int. J. Cancer., 2011, 129(1), 245-255.
http://dx.doi.org/10.1002/ijc.25864 PMID: 21170960
[155] Matsui, J.; Yamamoto, Y.; Funahashi, Y.; Tsuruoka, A.;
Watanabe, T.; Wakabayashi, T.; Uenaka, T.; Asada, M. E7080, a
novel inhibitor that targets multiple kinases, has potent antitumor
activities against stem cell factor producing human small cell lung
cancer H146, based on angiogenesis inhibition. Int. J. Cancer.,
2008, 122(3), 664-671.
http://dx.doi.org/10.1002/ijc.23131 PMID: 17943726
[156] Hilberg, F.; Roth, G.J.; Krssak, M.; Kautschitsch, S.; Sommer-
gruber, W.; Tontsch-Grunt, U.; Garin-Chesa, P.; Bader, G.; Zo-
ephel, A.; Quant, J.; Heckel, A.; Rettig, W.J. BIBF 1120: Triple
angiokinase inhibitor with sustained receptor blockade and good
antitumor efficacy. Cancer Res., 2008, 68(12), 4774-4782.
http://dx.doi.org/10.1158/0008-5472.CAN-07-6307 PMID:
18559524
[157] Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Cui, J.;
Fukuda, J.Y.; Chu, J.Y.; Nematalla, A.; Wang, X.; Chen, H.;
Sistla, A.; Luu, T.C.; Tang, F.; Wei, J.; Tang, C. Discovery of 5-
[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dime-
thyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a
novel tyrosine kinase inhibitor targeting vascular endothelial and
platelet-derived growth factor receptor tyrosine kinase. J. Med.
Chem., 2003, 46(7), 1116-1119.
http://dx.doi.org/10.1021/jm0204183 PMID: 12646019
[158] Abrams, T.J.; Murray, L.J.; Pesenti, E.; Holway, V.W.; Colombo,
T.; Lee, L.B.; Cherrington, J.M.; Pryer, N.K. Preclinical evalua-
tion of the tyrosine kinase inhibitor SU11248 as a single agent and
in combination with “standard of care” therapeutic agents for the
treatment of breast cancer. Mol. Cancer Ther., 2003, 2(10), 1011-
1021.
PMID: 14578466
[159] Mendel, D.B.; Laird, A.D.; Xin, X.; Louie, S.G.; Christensen,
J.G.; Li, G.; Schreck, R.E.; Abrams, T.J.; Ngai, T.J.; Lee, L.B.;
Murray, L.J.; Carver, J.; Chan, E.; Moss, K.G.; Haznedar, J.O.;
Sukbuntherng, J.; Blake, R.A.; Sun, L.; Tang, C.; Miller, T.; Shi-
razian, S.; McMahon, G.; Cherrington, J.M. In vivo antitumor ac-
tivity of SU11248, a novel tyrosine kinase inhibitor targeting vas-
cular endothelial growth factor and platelet-derived growth factor
receptors: Determination of a pharmacokinetic/pharmacodynamic
relationship. Clin. Cancer Res., 2003, 9(1), 327-337.
PMID: 12538485
[160] Yee, K.W.; Schittenhelm, M.; O’Farrell, A-M.; Town, A.R.;
McGreevey, L.; Bainbridge, T.; Cherrington, J.M.; Heinrich, M.C.
Synergistic effect of SU11248 with cytarabine or daunorubicin on
FLT3 ITD-positive leukemic cells. Blood., 2004, 104(13), 4202-
4209.
http://dx.doi.org/10.1182/blood-2003-10-3381 PMID: 15304385
[161] Ikezoe, T.; Nishioka, C.; Tasaka, T.; Yang, Y.; Komatsu, N.; Togi-
tani, K.; Koeffler, H.P.; Taguchi, H. The antitumor effects of
sunitinib (formerly SU11248) against a variety of human hemato-
logic malignancies: Enhancement of growth inhibition via inhibi-
tion of mammalian target of rapamycin signaling. Mol. Cancer
Ther., 2006, 5(10), 2522-2530.
http://dx.doi.org/10.1158/1535-7163.MCT-06-0071 PMID:
17041096
[162] Ghimirey, N.; Steele, C.; Czerniecki, B.J.; Koski, G.K.; Showalter,
L.E. Sunitinib combined with Th1 cytokines potentiates apoptosis
in human breast cancer cells and suppresses tumor growth in a mu-
rine model of HER-2pos breast cancer. Int. J. Breast Cancer., 2021,
2021, 8818393.
http://dx.doi.org/10.1155/2021/8818393 PMID: 33936816
[163] Mayer, E.L.; Dhakil, S.; Patel, T.; Sundaram, S.; Fabian, C.; Ko-
zloff, M.; Qamar, R.; Volterra, F.; Parmar, H.; Samant, M.;
Burstein, H.J. SABRE-B: An evaluation of paclitaxel and bevaci-
zumab with or without sunitinib as first-line treatment of metastat-
ic breast cancer. Ann. Oncol., 2010, 21(12), 2370-2376.
http://dx.doi.org/10.1093/annonc/mdq260 PMID: 20497961
VEGFRs as a Target in Breast Cancer
[164] Wildiers, H.; Fontaine, C.; Vuylsteke, P.; Martens, M.; Canon,
J.L.; Wynendaele, W.; Focan, C.; De Greve, J.; Squifflet, P.; Pari-
daens, R. Multicenter phase II randomized trial evaluating antian-
giogenic therapy with sunitinib as consolidation after objective re-
sponse to taxane chemotherapy in women with HER2-negative
metastatic breast cancer. Breast Cancer Res. Treat., 2010, 123(2),
463-469.
http://dx.doi.org/10.1007/s10549-010-1066-x PMID: 20652398
[165] Cardoso, F.; Canon, J-L.; Amadori, D.; Aldrighetti, D.; Machiels,
J-P.; Bouko, Y.; Verkh, L.; Usari, T.; Kern, K.A.; Giorgetti, C.;
Dirix, L. An exploratory study of sunitinib in combination with
docetaxel and trastuzumab as first-line therapy for HER2-positive
metastatic breast cancer. Breast., 2012, 21(6), 716-723.
http://dx.doi.org/10.1016/j.breast.2012.09.002 PMID: 23022045
[166] Bergh, J.; Bondarenko, I.M.; Lichinitser, M.R.; Liljegren, A.;
Greil, R.; Voytko, N.L.; Makhson, A.N.; Cortes, J.; Lortholary,
A.; Bischoff, J.; Chan, A.; Delaloge, S.; Huang, X.; Kern, K.A.;
Giorgetti, C. First-line treatment of advanced breast cancer with
sunitinib in combination with docetaxel versus docetaxel alone:
Results of a prospective, randomized phase III study. J. Clin. On-
col., 2012, 30(9), 921-929.
http://dx.doi.org/10.1200/JCO.2011.35.7376 PMID: 22331954
[167] Crown, J.P.; Diéras, V.; Staroslawska, E.; Yardley, D.A.;
Bachelot, T.; Davidson, N.; Wildiers, H.; Fasching, P.A.; Capitain,
O.; Ramos, M.; Greil, R.; Cognetti, F.; Fountzilas, G.; Blasinska-
Morawiec, M.; Liedtke, C.; Kreienberg, R.; Miller, W.H., Jr; Tas-
sell, V.; Huang, X.; Paolini, J.; Kern, K.A.; Romieu, G. Phase III
trial of sunitinib in combination with capecitabine versus capecita-
bine monotherapy for the treatment of patients with pretreated
metastatic breast cancer. J. Clin. Oncol., 2013, 31(23), 2870-2878.
http://dx.doi.org/10.1200/JCO.2012.43.3391 PMID: 23857972
[168] Barrios, C.H.; Liu, M-C.; Lee, S.C.; Vanlemmens, L.; Ferrero, J-
M.; Tabei, T.; Pivot, X.; Iwata, H.; Aogi, K.; Lugo-Quintana, R.;
Harbeck, N.; Brickman, M.J.; Zhang, K.; Kern, K.A.; Martin, M.
Phase III randomized trial of sunitinib versus capecitabine in pa-
tients with previously treated HER2-negative advanced breast can-
cer. Breast Cancer Res. Treat., 2010, 121(1), 121-131.
http://dx.doi.org/10.1007/s10549-010-0788-0 PMID: 20339913
[169] Wilhelm, S.M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.;
Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; Cao,
Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.; Rowley, B.; Liu, L.;
Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.; Voz-
nesensky, A.; Riedl, B.; Post, L.E.; Bollag, G.; Trail, P.A. BAY
43-9006 exhibits broad spectrum oral antitumor activity and tar-
gets the RAF/MEK/ERK pathway and receptor tyrosine kinases
involved in tumor progression and angiogenesis. Cancer Res.,
2004, 64(19), 7099-7109.
http://dx.doi.org/10.1158/0008-5472.CAN-04-1443 PMID:
15466206
[170] Liu, L.; Cao, Y.; Chen, C.; Zhang, X.; McNabola, A.; Wilkie, D.;
Wilhelm, S.; Lynch, M.; Carter, C. Sorafenib blocks the
RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induc-
es tumor cell apoptosis in hepatocellular carcinoma model
PLC/PRF/5. Cancer Res., 2006, 66(24), 11851-11858.
http://dx.doi.org/10.1158/0008-5472.CAN-06-1377 PMID:
17178882
[171] Ricci, M.S.; Kim, S-H.; Ogi, K.; Plastaras, J.P.; Ling, J.; Wang,
W.; Jin, Z.; Liu, Y.Y.; Dicker, D.T.; Chiao, P.J.; Flaherty, K.T.;
Smith, C.D.; El-Deiry, W.S. Reduction of TRAIL-induced Mcl-1
and cIAP2 by c-Myc or sorafenib sensitizes resistant human can-
cer cells to TRAIL-induced death. Cancer Cell., 2007, 12(1), 66-
80.
http://dx.doi.org/10.1016/j.ccr.2007.05.006 PMID: 17613437
[172] Zanotto-Filho, A.; Rajamanickam, S.; Loranc, E.; Masamsetti,
V.P.; Gorthi, A.; Romero, J.C.; Tonapi, S.; Gonçalves, R.M.; Red-
dick, R.L.; Benavides, R.; Kuhn, J.; Chen, Y.; Bishop, A.J.R. So-
rafenib improves alkylating therapy by blocking induced inflam-
mation, invasion and angiogenesis in breast cancer cells. Cancer
Lett., 2018, 425, 101-115.
http://dx.doi.org/10.1016/j.canlet.2018.03.037 PMID: 29608984
[173] Sui, J.; Cui, Y.; Cai, H.; Bian, S.; Xu, Z.; Zhou, L.; Sun, Y.; Liang,
J.; Fan, Y.; Zhang, X. Synergistic chemotherapeutic effect of so-
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 917
rafenib-loaded pullulan-Dox conjugate nanoparticles against mu-
rine breast carcinoma. Nanoscale., 2017, 9(8), 2755-2767.
http://dx.doi.org/10.1039/C6NR09639E PMID: 28155940
[174] Isaacs, C.; Herbolsheimer, P.; Liu, M.C.; Wilkinson, M.; Ottavi-
ano, Y.; Chung, G.G.; Warren, R.; Eng-Wong, J.; Cohen, P.;
Smith, K.L.; Creswell, K.; Novielli, A.; Slack, R. Phase I/II study
of sorafenib with anastrozole in patients with hormone receptor
positive aromatase inhibitor resistant metastatic breast cancer.
Breast Cancer Res. Treat., 2011, 125(1), 137-143.
http://dx.doi.org/10.1007/s10549-010-1226-z PMID: 20976541
[175] Moreno-Aspitia, A.; Morton, R.F.; Hillman, D.W.; Lingle, W.L.;
Rowland, K.M., Jr; Wiesenfeld, M.; Flynn, P.J.; Fitch, T.R.; Perez,
E.A. Phase II trial of sorafenib in patients with metastatic breast
cancer previously exposed to anthracyclines or taxanes: North cen-
tral cancer treatment group and mayo clinic trial N0336. J. Clin.
Oncol., 2009, 27(1), 11-15.
http://dx.doi.org/10.1200/JCO.2007.15.5242 PMID: 19047293
[176] Mina, L.A.; Yu, M.; Johnson, C.; Burkhardt, C.; Miller, K.D.;
Zon, R. A phase II study of combined VEGF inhibitor (bevaci-
zumab+sorafenib) in patients with metastatic breast cancer: Hoos-
ier oncology group study BRE06-109. Invest. New Drugs., 2013,
31(5), 1307-1310.
http://dx.doi.org/10.1007/s10637-013-9976-1 PMID: 23812905
[177] Mavratzas, A.; Baek, S.; Gerber, B.; Schmidt, M.; Moebus, V.;
Foerster, F.; Grischke, E.M.; Fasching, P.; Strumberg, D.; Solo-
mayer, E.; Klare, P.; Windemuth-Kieselbach, C.; Hartmann, S.;
Schneeweiss, A.; Marmé, F. Sorafenib in combination with docet-
axel as first-line therapy for HER2-negative metastatic breast can-
cer: Final results of the randomized, double-blind, placebo-
controlled phase II MADONNA study. Breast., 2019, 45, 22-28.
http://dx.doi.org/10.1016/j.breast.2019.02.002 PMID: 30822621
[178] Baselga, J; Zamagni, C; Gómez, P; Bermejo, B; Nagai, SE; Mel-
ichar, B RESILIENCE: Phase III randomized, double-blind trial
comparing sorafenib with capecitabine versus placebo with cape-
citabine in locally advanced or metastatic HER2-negative breast
cancer. Clin Breast Cancer., 2017, 17(8), 585-94.
http://dx.doi.org/10.1016/j.clbc.2017.05.006
[179] Wedge, S.R.; Ogilvie, D.J.; Dukes, M.; Kendrew, J.; Chester, R.;
Jackson, J.A.; Boffey, S.J.; Valentine, P.J.; Curwen, J.O.;
Musgrove, H.L.; Graham, G.A.; Hughes, G.D.; Thomas, A.P.;
Stokes, E.S.; Curry, B.; Richmond, G.H.; Wadsworth, P.F.;
Bigley, A.L.; Hennequin, L.F. ZD6474 inhibits vascular endothe-
lial growth factor signaling, angiogenesis, and tumor growth fol-
lowing oral administration. Cancer Res., 2002, 62(16), 4645-4655.
PMID: 12183421
[180] Ciardiello, F.; Caputo, R.; Damiano, V.; Caputo, R.; Troiani, T.;
Vitagliano, D.; Carlomagno, F.; Veneziani, B.M.; Fontanini, G.;
Bianco, A.R.; Tortora, G. Antitumor effects of ZD6474, a small
molecule vascular endothelial growth factor receptor tyrosine ki-
nase inhibitor, with additional activity against epidermal growth
factor receptor tyrosine kinase. Clin. Cancer Res., 2003, 9(4),
1546-1556.
PMID: 12684431
[181] Contrasted effects of the multitarget TKi vandetanib on docetaxel-
sensitive and docetaxel-resistant prostate cancer cell lines.Guérin,
O.; Etienne-Grimaldi, M-C.; Monteverde, M.; Sudaka, A.;
Brunstein, M-C.; Formento, P., Eds.; Urologic oncology: Semi-
nars and original investigations; Elsevier, 2013.
[182] Sarkar, S.; Rajput, S.; Tripathi, A.K.; Mandal, M. Targeted thera-
py against EGFR and VEGFR using ZD6474 enhances the thera-
peutic potential of UV-B phototherapy in breast cancer cells. Mol.
Cancer., 2013, 12(1), 122.
http://dx.doi.org/10.1186/1476-4598-12-122 PMID: 24138843
[183] Mayer, E.L.; Isakoff, S.J.; Klement, G.; Downing, S.R.; Chen,
W.Y.; Hannagan, K.; Gelman, R.; Winer, E.P.; Burstein, H.J.
Combination antiangiogenic therapy in advanced breast cancer: A
phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic
chemotherapy, with correlative platelet proteomics. Breast Cancer
Res. Treat., 2012, 136(1), 169-178.
http://dx.doi.org/10.1007/s10549-012-2256-5 PMID: 23001754
[184] Miller, K.D.; Trigo, J.M.; Wheeler, C.; Barge, A.; Rowbottom, J.;
Sledge, G.; Baselga, J. A multicenter phase II trial of ZD6474, a
918 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
vascular endothelial growth factor receptor-2 and epidermal
growth factor receptor tyrosine kinase inhibitor, in patients with
previously treated metastatic breast cancer. Clin. Cancer Res.,
2005, 11(9), 3369-3376.
http://dx.doi.org/10.1158/1078-0432.CCR-04-1923 PMID:
15867237
[185] Boér, K.; Láng, I.; Llombart-Cussac, A.; Andreasson, I.; Vivanco,
G.L.; Sanders, N.; Pover, G.M.; Murray, E. Vandetanib with
docetaxel as second-line treatment for advanced breast cancer: A
double-blind, placebo-controlled, randomized Phase II study. In-
vest. New Drugs., 2012, 30(2), 681-687.
http://dx.doi.org/10.1007/s10637-010-9538-8 PMID: 20830502
[186] Clemons, M.J.; Cochrane, B.; Pond, G.R.; Califaretti, N.; Chia,
S.K.; Dent, R.A.; Song, X.; Robidoux, A.; Parpia, S.; Warr, D.;
Rayson, D.; Pritchard, K.I.; Levine, M.N. Randomised, phase II,
placebo-controlled, trial of fulvestrant plus vandetanib in post-
menopausal women with bone only or bone predominant, hor-
mone-receptor-positive metastatic breast cancer (MBC): The
OCOG ZAMBONEY study. Breast Cancer Res. Treat., 2014,
146(1), 153-162.
http://dx.doi.org/10.1007/s10549-014-3015-6 PMID: 24924416
[187] Yakes, F.M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.;
Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.;
Laird, A.D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y.C.; Joly, A.H.
Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, sim-
ultaneously suppresses metastasis, angiogenesis, and tumor
growth. Mol. Cancer Ther., 2011, 10(12), 2298-2308.
http://dx.doi.org/10.1158/1535-7163.MCT-11-0264 PMID:
21926191
[188] You, W-K.; Sennino, B.; Williamson, C.W.; Falcón, B.;
Hashizume, H.; Yao, L-C.; Aftab, D.T.; McDonald, D.M. VEGF
and c-Met blockade amplify angiogenesis inhibition in pancreatic
islet cancer. Cancer Res., 2011, 71(14), 4758-4768.
http://dx.doi.org/10.1158/0008-5472.CAN-10-2527 PMID:
21613405
[189] Torres, K.E.; Zhu, Q-S.; Bill, K.; Lopez, G.; Ghadimi, M.P.; Xie,
X.; Young, E.D.; Liu, J.; Nguyen, T.; Bolshakov, S.; Belousov, R.;
Wang, S.; Lahat, G.; Liu, J.; Hernandez, B.; Lazar, A.J.; Lev, D.
Activated MET is a molecular prognosticator and potential thera-
peutic target for malignant peripheral nerve sheath tumors. Clin.
Cancer Res., 2011, 17(12), 3943-3955.
http://dx.doi.org/10.1158/1078-0432.CCR-11-0193 PMID:
21540237
[190] Tolaney, S.M.; Ziehr, D.R.; Guo, H.; Ng, M.R.; Barry, W.T.;
Higgins, M.J.; Isakoff, S.J.; Brock, J.E.; Ivanova, E.V.; Paweletz,
C.P.; Demeo, M.K.; Ramaiya, N.H.; Overmoyer, B.A.; Jain, R.K.;
Winer, E.P.; Duda, D.G. Phase II and biomarker study of cabozan-
tinib in metastatic triple‐negative breast cancer patients. Oncolo-
gist., 2017, 22(1), 25-32.
http://dx.doi.org/10.1634/theoncologist.2016-0229 PMID:
27789775
[191] Tolaney, S.M.; Nechushtan, H.; Ron, I-G.; Schöffski, P.; Awada,
A.; Yasenchak, C.A.; Laird, A.D.; O’Keeffe, B.; Shapiro, G.I.;
Winer, E.P. Cabozantinib for metastatic breast carcinoma: Results
of a phase II placebo-controlled randomized discontinuation study.
Breast Cancer Res. Treat., 2016, 160(2), 305-312.
http://dx.doi.org/10.1007/s10549-016-4001-y PMID: 27714541
[192] Shinagare, A.B.; Somarouthu, B.; Guo, H.; Tolaney, S.M.; Ramai-
ya, N.H. Occurrence and significance of morphologic changes in
patients with metastatic triple negative breast cancer treated with
Cabozantinib. Clin. Imaging., 2018, 48, 44-47.
http://dx.doi.org/10.1016/j.clinimag.2017.09.014 PMID:
29028513
[193] Leone, J.P.; Duda, D.G.; Hu, J.; Barry, W.T.; Trippa, L.; Gerstner,
E.R.; Jain, R.K.; Tan, S.; Lawler, E.; Winer, E.P.; Lin, N.U.; To-
laney, S.M. A phase II study of cabozantinib alone or in combina-
tion with trastuzumab in breast cancer patients with brain metasta-
ses. Breast Cancer Res. Treat., 2020, 179(1), 113-123.
http://dx.doi.org/10.1007/s10549-019-05445-z PMID: 31541381
[194] Tian, S.; Quan, H.; Xie, C.; Guo, H.; Lü, F.; Xu, Y.; Li, J.; Lou, L.
YN968D1 is a novel and selective inhibitor of vascular endothelial
Malekan and Ebrahimzadeh
growth factor receptor-2 tyrosine kinase with potent activity in
vitro and in vivo. Cancer Sci., 2011, 102(7), 1374-1380.
http://dx.doi.org/10.1111/j.1349-7006.2011.01939.x PMID:
21443688
[195] Mi, Y.J.; Liang, Y.J.; Huang, H.B.; Zhao, H.Y.; Wu, C-P.; Wang,
F.; Tao, L.Y.; Zhang, C.Z.; Dai, C.L.; Tiwari, A.K.; Ma, X.X.; To,
K.K.; Ambudkar, S.V.; Chen, Z.S.; Fu, L.W. Apatinib (YN968D1)
reverses multidrug resistance by inhibiting the efflux function of
multiple ATP-binding cassette transporters. Cancer Res., 2010,
70(20), 7981-7991.
http://dx.doi.org/10.1158/0008-5472.CAN-10-0111 PMID:
20876799
[196] Zhang, H.; Sun, J.; Ju, W.; Li, B.; Lou, Y.; Zhang, G.; Liang, G.;
Luo, X. Apatinib suppresses breast cancer cells proliferation and
invasion via angiomotin inhibition. Am. J. Transl. Res., 2019,
11(7), 4460-4469.
PMID: 31396349
[197] Gao, Z.; Shi, M.; Wang, Y.; Chen, J.; Ou, Y. Apatinib enhanced
anti-tumor activity of cisplatin on triple-negative breast cancer
through inhibition of VEGFR-2. Pathol. Res. Pract., 2019, 215(7),
152422.
http://dx.doi.org/10.1016/j.prp.2019.04.014 PMID: 31079851
[198] Tong, X.Z.; Wang, F.; Liang, S.; Zhang, X.; He, J.H.; Chen, X-G.;
Liang, Y.J.; Mi, Y.J.; To, K.K.; Fu, L.W. Apatinib (YN968D1)
enhances the efficacy of conventional chemotherapeutical drugs in
side population cells and ABCB1-overexpressing leukemia cells.
Biochem. Pharmacol., 2012, 83(5), 586-597.
http://dx.doi.org/10.1016/j.bcp.2011.12.007 PMID: 22212563
[199] Zhu, A.; Yuan, P.; Hu, N.; Li, M.; Wang, W.; Wang, X.; Yue, J.;
Wang, J.; Luo, Y.; Ma, F.; Zhang, P.; Li, Q.; Xu, B.; Cao, S.; Lip-
pi, G.; Naito, Y.; Osman, M.A.; Marta, G.N.; Franceschini, G.; Or-
landi, A. Phase II study of apatinib in combination with oral vi-
norelbine in heavily pretreated HER2-negative metastatic breast
cancer and clinical implications of monitoring ctDNA. Cancer Bi-
ol. Med., 2021, 18(3), 875-887.
http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0418 PMID:
34037346
[200] Hu, X.; Cao, J.; Hu, W.; Wu, C.; Pan, Y.; Cai, L.; Tong, Z.; Wang,
S.; Li, J.; Wang, Z.; Wang, B.; Chen, X.; Yu, H. Multicenter phase
II study of apatinib in non-triple-negative metastatic breast cancer.
BMC Cancer., 2014, 14(1), 820.
http://dx.doi.org/10.1186/1471-2407-14-820 PMID: 25376790
[201] Fan, M.; Zhang, J.; Wang, Z.; Wang, B.; Zhang, Q.; Zheng, C.; Li,
T.; Ni, C.; Wu, Z.; Shao, Z.; Hu, X. Phosphorylated VEGFR2 and
hypertension: Potential biomarkers to indicate VEGF-dependency
of advanced breast cancer in anti-angiogenic therapy. Breast Can-
cer Res. Treat., 2014, 143(1), 141-151.
http://dx.doi.org/10.1007/s10549-013-2793-6 PMID: 24292957
[202] Ou, K.P.; Li, Q.; Luo, Y.; Lyu, J.J.; Zhou, H.; Yang, Y.; Cai, Y.J.;
Wang, Z.J.; Wang, X.; Qi, L.Q.; Ma, F.; Xu, B.H. Efficacy and
safety of neoadjuvant apatinib in combination with dose-dense
paclitaxel and carboplatin in locally advanced triple negative
breast cancer patients. Zhonghua Zhong Liu Za Zhi., 2020, 42(11),
966-971.
PMID: 33256310
[203] Fong, T.A.T.; Shawver, L.K.; Sun, L.; Tang, C.; App, H.; Powell,
T.J.; Kim, Y.H.; Schreck, R.; Wang, X.; Risau, W.; Ullrich, A.;
Hirth, K.P.; McMahon, G. SU5416 is a potent and selective inhibi-
tor of the vascular endothelial growth factor receptor (Flk-1/KDR)
that inhibits tyrosine kinase catalysis, tumor vascularization, and
growth of multiple tumor types. Cancer Res., 1999, 59(1), 99-106.
PMID: 9892193
[204] Vajkoczy, P.; Menger, M.D.; Vollmar, B.; Schilling, L.;
Schmiedek, P.; Hirth, K.P.; Ullrich, A.; Fong, T.A. Inhibition of
tumor growth, angiogenesis, and microcirculation by the novel
Flk-1 inhibitor SU5416 as assessed by intravital multi-
fluorescence videomicroscopy. Neoplasia., 1999, 1(1), 31-41.
http://dx.doi.org/10.1038/sj.neo.7900006 PMID: 10935468
[205] Overmoyer, B.; Fu, P.; Hoppel, C.; Radivoyevitch, T.; Shenk, R.;
Persons, M.; Silverman, P.; Robertson, K.; Ziats, N.P.; Wasman,
J.K.; Abdul-Karim, F.W.; Jesberger, J.A.; Duerk, J.; Hartman, P.;
VEGFRs as a Target in Breast Cancer
Hanks, S.; Lewin, J.; Dowlati, A.; McCrae, K.; Ivy, P.; Remick,
S.C. Inflammatory breast cancer as a model disease to study tumor
angiogenesis: Results of a phase IB trial of combination SU5416
and doxorubicin. Clin. Cancer Res., 2007, 13(19), 5862-5868.
http://dx.doi.org/10.1158/1078-0432.CCR-07-0688 PMID:
17908980
[206] Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.;
Tang, C. Synthesis and biological evaluations of 3-substituted in-
dolin-2-ones: A novel class of tyrosine kinase inhibitors that ex-
hibit selectivity toward particular receptor tyrosine kinases. J.
Med. Chem., 1998, 41(14), 2588-2603.
http://dx.doi.org/10.1021/jm980123i PMID: 9651163
[207] Kataoka, Y.; Mukohara, T.; Tomioka, H.; Funakoshi, Y.; Kiyota,
N.; Fujiwara, Y.; Yashiro, M.; Hirakawa, K.; Hirai, M.; Minami,
H. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and
VEGFRs, inhibits growth of gastric cancer cell lines by blocking
inter-receptor tyrosine kinase networks. Invest. New Drugs., 2012,
30(4), 1352-1360.
http://dx.doi.org/10.1007/s10637-011-9699-0 PMID: 21655918
[208] Qian, F.; Engst, S.; Yamaguchi, K.; Yu, P.; Won, K-A.; Mock, L.;
Lou, T.; Tan, J.; Li, C.; Tam, D.; Lougheed, J.; Yakes, F.M.;
Bentzien, F.; Xu, W.; Zaks, T.; Wooster, R.; Greshock, J.; Joly,
A.H. Inhibition of tumor cell growth, invasion, and metastasis by
EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and
VEGF receptor tyrosine kinases. Cancer Res., 2009, 69(20), 8009-
8016.
http://dx.doi.org/10.1158/0008-5472.CAN-08-4889 PMID:
19808973
[209] Rayson, D.; Lupichuk, S.; Potvin, K.; Dent, S.; Shenkier, T.;
Dhesy-Thind, S.; Ellard, S.L.; Prady, C.; Salim, M.; Farmer, P.;
Allo, G.; Tsao, M.S.; Allan, A.; Ludkovski, O.; Bonomi, M.; Tu,
D.; Hagerman, L.; Goodwin, R.; Eisenhauer, E.; Bradbury, P. Ca-
nadian cancer trials group IND197: A phase II study of foretinib in
patients with estrogen receptor, progesterone receptor, and human
epidermal growth factor receptor 2-negative recurrent or metastat-
ic breast cancer. Breast Cancer Res. Treat., 2016, 157(1), 109-
116.
http://dx.doi.org/10.1007/s10549-016-3812-1 PMID: 27116183
[210] Chia, S.K.; Ellard, S.L.; Mates, M.; Welch, S.; Mihalcioiu, C.;
Miller, W.H., Jr; Gelmon, K.; Lohrisch, C.; Kumar, V.; Taylor, S.;
Hagerman, L.; Goodwin, R.; Wang, T.; Sakashita, S.; Tsao, M.S.;
Eisenhauer, E.; Bradbury, P. A phase-I study of lapatinib in com-
bination with foretinib, a c-MET, AXL and vascular endothelial
growth factor receptor inhibitor, in human epidermal growth factor
receptor 2 (HER-2)-positive metastatic breast cancer. Breast Can-
cer Res., 2017, 19(1), 54.
http://dx.doi.org/10.1186/s13058-017-0836-3 PMID: 28464908
[211] Zhou, S.; Liao, H.; Liu, M.; Feng, G.; Fu, B.; Li, R.; Cheng, M.;
Zhao, Y.; Gong, P. Discovery andw biological evaluation of novel
6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives pos-
sessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase in-
hibitors. Bioorg. Med. Chem., 2014, 22(22), 6438-6452.
http://dx.doi.org/10.1016/j.bmc.2014.09.037 PMID: 25438768
[212] Bhide, R.S.; Cai, Z-W.; Zhang, Y-Z.; Qian, L.; Wei, D.; Barbosa,
S.; Lombardo, L.J.; Borzilleri, R.M.; Zheng, X.; Wu, L.I.; Barrish,
J.C.; Kim, S.H.; Leavitt, K.; Mathur, A.; Leith, L.; Chao, S.;
Wautlet, B.; Mortillo, S.; Jeyaseelan, R., Sr; Kukral, D.; Hunt,
J.T.; Kamath, A.; Fura, A.; Vyas, V.; Marathe, P.; D’Arienzo, C.;
Derbin, G.; Fargnoli, J. Discovery and preclinical studies of (R)-1-
(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-
f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo ac-
tive potent VEGFR-2 inhibitor. J. Med. Chem., 2006, 49(7), 2143-
2146.
http://dx.doi.org/10.1021/jm051106d PMID: 16570908
[213] Huynh, H.; Ngo, V.C.; Fargnoli, J.; Ayers, M.; Soo, K.C.; Koong,
H.N.; Thng, C.H.; Ong, H.S.; Chung, A.; Chow, P.; Pollock, P.;
Byron, S.; Tran, E. Brivanib alaninate, a dual inhibitor of vascular
endothelial growth factor receptor and fibroblast growth factor re-
ceptor tyrosine kinases, induces growth inhibition in mouse mod-
els of human hepatocellular carcinoma. Clin. Cancer Res., 2008,
14(19), 6146-6153.
Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11 919
http://dx.doi.org/10.1158/1078-0432.CCR-08-0509 PMID:
18829493
[214] Patel, R.R.; Sengupta, S.; Kim, H.R.; Klein-Szanto, A.J.; Pyle,
J.R.; Zhu, F.; Li, T.; Ross, E.A.; Oseni, S.; Fargnoli, J.; Jordan,
V.C. Experimental treatment of oestrogen receptor (ER) positive
breast cancer with tamoxifen and brivanib alaninate, a VEGFR-
2/FGFR-1 kinase inhibitor: A potential clinical application of an-
giogenesis inhibitors. Eur. J. Cancer., 2010, 46(9), 1537-1553.
http://dx.doi.org/10.1016/j.ejca.2010.02.018 PMID: 20303261
[215] Schöffski, P.; Gordon, M.; Smith, D.C.; Kurzrock, R.; Daud, A.;
Vogelzang, N.J.; Lee, Y.; Scheffold, C.; Shapiro, G.I. Phase II
randomised discontinuation trial of cabozantinib in patients with
advanced solid tumours. Eur. J. Cancer., 2017, 86, 296-304.
http://dx.doi.org/10.1016/j.ejca.2017.09.011 PMID: 29059635
[216] Wang, X.; Sinn, A.L.; Pollok, K.; Sandusky, G.; Zhang, S.; Chen,
L.; Liang, J.; Crean, C.D.; Suvannasankha, A.; Abonour, R.; Sidor,
C.; Bray, M.R.; Farag, S.S. Preclinical activity of a novel multiple
tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against
multiple myeloma. Br. J. Haematol., 2010, 150(3), 313-325.
http://dx.doi.org/10.1111/j.1365-2141.2010.08248.x PMID:
20560971
[217] Fletcher, G.C.; Brokx, R.D.; Denny, T.A.; Hembrough, T.A.;
Plum, S.M.; Fogler, W.E.; Sidor, C.F.; Bray, M.R. ENMD-2076 is
an orally active kinase inhibitor with antiangiogenic and antipro-
liferative mechanisms of action. Mol. Cancer Ther., 2011, 10(1),
126-137.
http://dx.doi.org/10.1158/1535-7163.MCT-10-0574 PMID:
21177375
[218] Ionkina, A.A.; Tentler, J.J.; Kim, J.; Capasso, A.; Pitts, T.M.;
Ryall, K.A.; Howison, R.R.; Kabos, P.; Sartorius, C.A.; Tan, A.C.;
Eckhardt, S.G.; Diamond, J.R. Efficacy and molecular mecha-
nisms of differentiated response to the Aurora and angiogenic ki-
nase inhibitor ENMD-2076 in preclinical models of p53-mutated
triple-negative breast cancer. Front. Oncol., 2017, 7, 94.
http://dx.doi.org/10.3389/fonc.2017.00094 PMID: 28555173
[219] Diamond, J.R.; Eckhardt, S.G.; Tan, A.C.; Newton, T.P.; Selby,
H.M.; Brunkow, K.L.; Kachaeva, M.I.; Varella-Garcia, M.; Pitts,
T.M.; Bray, M.R.; Fletcher, G.C.; Tentler, J.J. Predictive bi-
omarkers of sensitivity to the aurora and angiogenic kinase inhibi-
tor ENMD-2076 in preclinical breast cancer models. Clin. Cancer
Res., 2013, 19(1), 291-303.
http://dx.doi.org/10.1158/1078-0432.CCR-12-1611 PMID:
23136197
[220] Diamond, J.R.; Eckhardt, S.G.; Pitts, T.M.; van Bokhoven, A.;
Aisner, D.; Gustafson, D.L.; Capasso, A.; Sams, S.; Kabos, P.;
Zolman, K.; Colvin, T.; Elias, A.D.; Storniolo, A.M.; Schneider,
B.P.; Gao, D.; Tentler, J.J.; Borges, V.F.; Miller, K.D. A phase II
clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-
2076 for previously treated, advanced, or metastatic triple-negative
breast cancer. Breast Cancer Res., 2018, 20(1), 82.
http://dx.doi.org/10.1186/s13058-018-1014-y PMID: 30071865
[221] Shao, W.; Li, S.; Li, L.; Lin, K.; Liu, X.; Wang, H.; Wang, H.;
Wang, D. Chemical genomics reveals inhibition of breast cancer
lung metastasis by Ponatinib via c-Jun. Protein Cell., 2019, 10(3),
161-177.
http://dx.doi.org/10.1007/s13238-018-0533-8 PMID: 29667003
[222] Ye, T.; Wei, X.; Yin, T.; Xia, Y.; Li, D.; Shao, B.; Song, X.; He,
S.; Luo, M.; Gao, X.; He, Z.; Luo, C.; Xiong, Y.; Wang, N.; Zeng,
J.; Zhao, L.; Shen, G.; Xie, Y.; Yu, L.; Wei, Y. Inhibition of FGFR
signaling by PD173074 improves antitumor immunity and impairs
breast cancer metastasis. Breast Cancer Res. Treat., 2014, 143(3),
435-446.
http://dx.doi.org/10.1007/s10549-013-2829-y PMID: 24398778
[223] O’Hare, T.; Shakespeare, W.C.; Zhu, X.; Eide, C.A.; Rivera,
V.M.; Wang, F.; Adrian, L.T.; Zhou, T.; Huang, W.S.; Xu, Q.;
Metcalf, C.A., III; Tyner, J.W.; Loriaux, M.M.; Corbin, A.S.;
Wardwell, S.; Ning, Y.; Keats, J.A.; Wang, Y.; Sundaramoorthi,
R.; Thomas, M.; Zhou, D.; Snodgrass, J.; Commodore, L.; Saw-
yer, T.K.; Dalgarno, D.C.; Deininger, M.W.; Druker, B.J.; Clack-
son, T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid
leukemia, potently inhibits the T315I mutant and overcomes muta-
tion-based resistance. Cancer Cell., 2009, 16(5), 401-412.
920 Current Topics in Medicinal Chemistry, 2022, Vol. 22, No. 11
http://dx.doi.org/10.1016/j.ccr.2009.09.028 PMID: 19878872
[224] Huang, W-S.; Metcalf, C.A.; Sundaramoorthi, R.; Wang, Y.; Zou,
D.; Thomas, R.M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; Romero, J.;
Qi, J.; Chen, I.; Banda, G.; Lentini, S.P.; Das, S.; Xu, Q.; Keats, J.;
Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J.T.; Broudy, M.I.;
Russian, K.; Zhou, T.; Commodore, L.; Narasimhan, N.I.; Mo-
hemmad, Q.K.; Iuliucci, J.; Rivera, V.M.; Dalgarno, D.C.; Sawyer,
T.K.; Clackson, T.; Shakespeare, W.C. Discovery of 3-[2-
(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-4-[(4-
methylpiperazin-1-yl)methyl]-3-
(trifluoromethyl)phenylbenzamide (AP24534), a potent, orally ac-
tive pan-inhibitor of breakpoint cluster region-abelson (BCR-
ABL) kinase including the T315I gatekeeper mutant. J. Med.
Chem., 2010, 53(12), 4701-4719.
http://dx.doi.org/10.1021/jm100395q PMID: 20513156
[225] Hamby, J.M.; Connolly, C.J.; Schroeder, M.C.; Winters, R.T.;
Showalter, H.D.; Panek, R.L.; Major, T.C.; Olsewski, B.; Ryan,
M.J.; Dahring, T.; Lu, G.H.; Keiser, J.; Amar, A.; Shen, C.;
Kraker, A.J.; Slintak, V.; Nelson, J.M.; Fry, D.W.; Bradford, L.;
Malekan and Ebrahimzadeh
Hallak, H.; Doherty, A.M. Structure-activity relationships for a
novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors.
J. Med. Chem., 1997, 40(15), 2296-2303.
http://dx.doi.org/10.1021/jm970367n PMID: 9240345
[226] Cee, V.J.; Albrecht, B.K.; Geuns-Meyer, S.; Hughes, P.; Bellon,
S.; Bready, J.; Caenepeel, S.; Chaffee, S.C.; Coxon, A.; Emery,
M.; Fretland, J.; Gallant, P.; Gu, Y.; Hodous, B.L.; Hoffman, D.;
Johnson, R.E.; Kendall, R.; Kim, J.L.; Long, A.M.; McGowan, D.;
Morrison, M.; Olivieri, P.R.; Patel, V.F.; Polverino, A.; Powers,
D.; Rose, P.; Wang, L.; Zhao, H. Alkynylpyrimidine amide deriva-
tives as potent, selective, and orally active inhibitors of Tie-2 ki-
nase. J. Med. Chem., 2007, 50(4), 627-640.
http://dx.doi.org/10.1021/jm061112p PMID: 17253679
[227] Mohammadi, M.; Froum, S.; Hamby, J.M.; Schroeder, M.C.;
Panek, R.L.; Lu, G.H.; Eliseenkova, A.V.; Green, D.;
Schlessinger, J.; Hubbard, S.R. Crystal structure of an angiogene-
sis inhibitor bound to the FGF receptor tyrosine kinase domain.
EMBO J., 1998, 17(20), 5896-5904.
http://dx.doi.org/10.1093/emboj/17.20.5896 PMID: 9774334