02 Egfr-Her2 Vegfr Inhibitor

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非法與侵權等相關事宜，概由不當使用者負完全責任
表皮生長因子受體（EGFR, epidermal growth factor receptor, HER1）
人類表皮生長因子受體2（Human Epidermal Growth Factor Receptor 2）
 EGFR and HER2 are closely related membrane-bound TKs.
 EGFR expression in solid tumors of the breast, lung, bladder, esophagus, and oral cavity has been
clearly correlated with decreased life expectancy
 consistent presence in almost all epithelial-derived cancers.
 HER2 overexpression is a classic feature of treatment-resistant breast, ovarian, lung, and gastric
cancers 在EGFR第20個外顯子上，第790位點的T被Ｍ取代，影響
了EGFR激酶的ATP結合區。Ｔ是具極性小型胺基酸；而Ｍ
 endows tumors with what’s been called an “antiapoptotic shield.”
是非極性較大胺基酸。T790M增加ATP與EGFR活性部位的
親和力，使ATP比抑制劑更具結合優勢
 the efficacy of EGFR/HER2 inhibitors can be thwarted受阻by mutations in the “gatekeeper”
(Thr790) residue, specifically T790M (Thr790Met).
 therapeutically challenging genetic transformation is approximately 60% of resistant NSCLC
 osimertinib, a structure containing a terminal electrophilic target for the nucleophilic Cys797, is an effective
inhibitor of T790M-positive EGFR, and has provided new hope to NSCLC patients.
3
• Type I inhibitors
• compete with ATP and bind in its active form.
• Type II inhibitors
• bind to the inactive kinase conformer.
• Type III inhibitors
• fit into an allosteric pocket adjacent to the active site.
• Type IV inhibitors
• bind to an allosteric binding site distant from the ATP‐binding site.
Irreversible Kinase Inhibitors
1. Adenine pocket: heterocyclic ring
2. Hydrophobic pocket
Acrylamide
Michael alkylating inhibitor
3. Allosteric pocket (DFG trio)
4. Solvent region
4
7
6 4
3’
4’
4-anilinoquinazoline
5
REVERSIBLE
 contain a 4-anilinoquinazoline pharmacophore with an
oxygen-containing substituent at C6
 Ether-containing moieties of varying size are also permitted at C7
 An electron-withdrawing substituent at position 3′ of the aniline phenyl ring provides high selectivity for EGFR
kinase as long as the 4′ position remains unsubstituted (erlotinib) or is modified with a very small substituent
such as fluorine (gefitinib).
 Erlotinib and gefitinib are quintessential典型 type I TKIs, with the m-substituted phenyl ring of the aniline moiety
enhancing affinity through binding with hydrophobic pocket residues of the active (open) enzyme.
 The H-bonds formed between the quinazoline nitrogen atoms and hinge residues Met793 (N1) and Thr790
(N3) are crucial to activity.
 The halogenated and acetylene-substituted phenyl rings of gefitinib and erlotinib are maintained at a 42-
degree angle relative to the quinazoline ring
 bind well in the hydrophobic pocket near Thr790 as long as this gatekeeper residue remains small.
6
 Increasing the size of the 4′ substituent with groups like m-fluorobenzyloxy (lapatinib) restricts
access to only the inactive conformation of EGFR and broadens TK specificity to include HER2.
5
methylsulfone
4′ morpholine
m‐fluorobenzyloxy
 Water solubility
 Lapatinib’s 2-furanyl substituent can be further substituted at position 5 with long, unbranched chains
that extend out into the aqueous environment.
 The addition of a methylsulfone moiety to the chain terminus enhances water solubility.
 The ionizable morpholine ring of gefitinib serves a similar purpose, as should the strongly basic moieties
of vandetanib (piperidine), afatinib, and neratinib (dimethylamine).

 The water solubility of erlotinib is predictably low given the relative lack of polar functional groups in this area of the
molecule.
7
IRREVERSIBLE
 Cys797 residue is located within the ATP-binding domain of EFGR and HER2
 Afatinib as the model Michael alkylating inhibitor, the SH group of Cys797 is positioned to
conduct a nucleophilic attack at the electrophilic terminal carbon of the acrylamide, forming the
irreversibly bound adduct.
 Osimertinib and neratinib also contain this electrophilic moiety within their structures
Cys797
acrylamide
8
 with an unsubstituted aniline moiety (e.g., erlotinib),
 direct CYP-mediated hydroxylation generates a p-hydroxyaniline
group that is vulnerable to further CYP-catalyzed oxidation to the
electrophilic quinoneimine
 the p-position is blocked by halogen can undergo

oxidative dehalogenation followed by hydroxylation to the
labile p-hydroxyaniline (e.g., gefitinib).
 o-Cl group increases the electrophilic character of the ring, making it
more vulnerable to attack by reduced glutathione (GSH)
 afatinib is resistant to CYP-mediated metabolism
 p-bromo group of vandetanib is stable in vivo (p.9). afatinib
9
Metabolites of vandetanib
10
11
 NSCLC cancer in patients whose disease has either stabilized after four rounds of
organoplatinum therapy or progressed after completion of a non–TKI-based
chemotherapeutic regimen.
 Combine with the DNA polymerase inhibitor gemcitabine as first-line therapy in

advanced or metastatic pancreatic cancer
 more effective in tumors expressing activating ex19del or exon 21 L858R mutations kinase
 equally effective with gefitinib and afatinib when used as first-line therapy in NSCLC
 CYP3A4 O-dealkylation of the methoxy of the C6 side chain, the 1o alcohol are oxidized to the
carboxylic acid
 Toxicity
 The maculopapular rash positively correlated with therapeutic efficacy , worsens when exposed to sunlight.
斑丘疹
 Hepatotoxicity risk
12
 Resistance: P-gp substrate
 used in the treatment of NSCLC that presents with ex19del or L858R mutation.
 EGFR is often robustly expressed強烈表現 in this neoplastic disease.
 Resistance generally develops at 10 months, due to the development of the T790M mutation.
 poor 2D6 metabolizers are at increased risk for the characteristic EGFR kinase inhibitor-
induced rash
 Cigarette smoking induces CYP1A1 (p.13)

 speeds metabolic inactivation of gefitinib, poor response, increased risk of quinoneimine-induced
interstitial lung disease and hepatotoxicity.
 Smokers can generate up to 12 times more reactive quinoneimine metabolite than nonsmokers.
 induces aberrant eyelash growth which can induce eye pain

13
14
 dual kinase inhibitor with affinity for both EGFR and HER2
 Lapatinib inhibits P-gp and BCRP (breast cancer resistance protein)
 combined with the pyrimidine antagonist capecitabine or the aromatase
inhibitor letrozole in HER2+ breast cancer patients (25%-30%) failed on first-line

1
therapies, including the MAb trastuzumab that targets HER2.
 HER2 overexpression in breast cancer is associated with poor prognosis and

2
limited survival, lapatinib is one of only two TKIs available to treat it.
 very expensive (approximately $1,500 per month)
15
 CYP3A4-catalyzed dealkylation of the m-fluorobenzyl moiety sets the metabolic
stage for oxidation to the hepatotoxic quinoneimine.
O‐dealkylation
16
 one of only a few targeted therapies available to attenuate cell proliferation, halt
angiogenesis, and slow tumor growth in this aggressive disease.
 in addition to EGFR, inhibits VEGFR, rearranged during transfection (RET) proto-oncogene, and
SRC. RET是酪胺酸激酶接受器，RET基因融合變異會促進癌症細胞生長。原致癌基
因（proto‐oncogene）為細胞內正常基因，其表現的蛋白質產物能促進細胞生
Src 基因是第一個被發現的致癌基因，使雞長出長及分裂，當放射性、化學物質及病毒作用而致突變，造成其蛋白質產物過
sarcoma的基因，其命名Src取自肉瘤英文 sarcoma 量產生或活性增加，使細胞生長及分裂大幅增加而導致癌症。
 Due to the risk of life-threatening adverse effects, including sudden cardiac death,
vandetanib is only available to trained providers through the Risk Evaluation and
Mitigation Strategy (REMS) program.
 Resistance
 RET expression/function (e.g., mutation)
 activation of downstream signaling pathways.
17
 active N-demethylated metabolite
 inactivating FMO (Flavin mono-oxygenase)-catalyzed N-oxdation.
18
 second-generation EGFR kinase inhibitor approved as first-line therapy for treatment of NSCLC
 developed non-resistant mutations which can render first-generation agents erlotinib and gefitinib ineffective
within a year’s time.
 forms a covalent bond with Cys797 on EGFR (and with Cys805 and Cys803 of HER2 and HER4,
respectively) to irreversibly inactivate the kinase
 increase OS 整體存活率(Overall survival) in squamous鱗狀細胞癌NSCLC compared to erlotinib
 effective in ex19del and L858R mutants, promotes OS in patients with ex19del mutations, and may delay
manifestation of the drug-resistant T790M mutation
 Acquired resistance : Janus-activated kinase-1 (JAK1), combined with JAK1 inhibitors has been
suggested.
 substrate and mild inhibitor of P-gp and BCRP

19
 therapeutic indication is similar to lapatinib (HER2+ breast cancer in patients

previously administered trastuzumab),
 the electrophilic acrylamide within its structure assures that its antineoplastic mechanism mirrors
that of afatinib (p.20)
 irreversible kinase inhibition through covalent bond formation with a Cys residue; Cys805 in HER2.
 25%-30% of breast cancer patients will experience disease recurrence within

10 years, with the current standard of care (presurgical chemotherapy, surgery,
trastuzumab), neratinib has shown promise when used either pre- or postsurgery
 binds to a different HER2 domain than trastuzumab
 no cross resistance with the MAb and coadministration can be beneficial
20
 metabolized by CYP3A4  Three active metabolites
 N-oxides of the pyridine (M3)

 to a lesser extent by FMO.
 dimethylamine (M7) moieties
 monodesmethyl secondary amine (M6).
 M7 is the metabolite generated by FMO.
acrylamide
21
 an acrylamide-containing third-generation irreversible TKI

 as second-line therapy for T790M positive metastatic NSCLC that has progressed after treatment
with a first- or second-generation TKI.
 therapeutic efficacy in T790M positive NSCLC

 promotes PFS 疾病無惡化存活期(Progression‐free survival) in T790M positive patients compared to
alternative therapies (e.g., organoplatinum-antifolate), significantly decreases the risk of death, and
can elicit clinical responses in patients with commonly encountered central metastases due to its
ability to penetrate the blood-brain barrier (BBB).
 CYP3A4 catalyzes osimertinib N-dealkylation at the indole and terminal amine moieties,
generating two active metabolites known as AZ5104 and AZ7550 (p.22)
N‐dealkylation
 substrate of P-gp, but not OCT1 N‐dealkylation
22
acrylamide
FIGURE 33.2 Active metabolites
of tyrosine kinase inhibitors.
23
IRREVERSIBLE
 EGFR/HER kinase inhibitors  Bruton tyrosine kinase inhibitors
 Afatinib  Ibrutinib
 Neratinib  Acalabrutinib
 Osimertinib
acrylamide
24
25
血管內皮細胞生長因子受體 Vascular Endothelial Growth Factor Receptor
 Three VEGFR isoforms bind the angiogenesis-promoting VEGF protein,
resulting in the development of new blood vessels that supply oxygen and
nutrients to growing neoplasms • Angiogenesis指芽生性（Sprouting）血管新生，新生血管由舊
有血管衍生而來，主要是後天生理過程
• Vasculogenesis是由無到有的血管新生過程，新生血管是由血管
前驅性細胞或各種幹細胞分化而來，主要存在於胚胎發育過程。
 VEGF inhibition decreases the permeability of tumor cell vasculature and eases
intracellular delivery of chemotherapeutic agents

 starve malignant cells and block the production of metastatic highways
26
• Sunitinib’s indolinone
• pazopanib’s pyrimidine-2-amino
• lenvatinib’s quinoline
ATP-binding hinge region

indazole
1. Adenine pocket: heterocyclic ring
2. Hydrophobic pocket: phenyl ring
pyridylvinyl
3. Allosteric pocket (DFG trio):
trifluoromethyl phenyl, benzamide group
4. Solvent region: pyridylvinyl moiety
(axitinib); not solvated (soratinib)
H-bond
ATP-binding hinge region
FIGURE 33.8 Binding interactions between VEGFR tyrosine kinase and representative inhibitors. 27
 Geometric isomerism is important to the TKI activity of sunitinib
 with the lower energy Z isomer being over 100 times as potent as the higher energy E isomer
 marketed in its pure eutomeric (Z) form
 Only the E isomer of axitinib is marketed

Sunitinib  Z
優先序大
優先序大
優先序大
優先序大的基團在雙鍵同側Z
Axitinib  E
優先序大的基團在雙鍵異側E 優先序大
28
29
indicated for use in advanced renal cell carcinoma (RCC)晚期腎細胞癌
 the first TKI approved to treat metastatic RCC
 its affinity for multiple kinases (including RAF, RET, c-kit and FLT3, in addition to VEGFR) is important to its activity
 a milder adverse effect profile when compared to other targeted agents, its use is not restricted to second-line therapy
 the first TKI approved for the treatment of radioactive iodine refractory advanced differentiated thyroid
cancer (放射性碘難治性晚期分化型甲狀腺癌)
 a type of thyroid cancer with a poor prognosis (3-5 yr median survival)
 CYP3A4 inducers and inhibitors should not be coadministered if at all possible
 CYP3A4 oxidizes sorafenib to a similarly active N-oxide metabolite
 the glucuronide conjugate that forms as a result of UGT1A9 catalysis can be cleaved in the gut, resulting in the recycling
of active drug
 distribution is restricted and prescriptions must be filled at specialty pharmacies. Only patients enrolled in the
Resources for Expert Assistance and Care Helpline (REACH) program can receive this drug
30
 a positive alternative to sorafenib in patients with differentiated thyroid cancer
 inhibits tumor growth through its antiangiogenic action
 low drug-drug interaction liability and does not require dosing adjustments in
patients coadministered inhibitors or inducers of these proteins

 No metabolites are active
 BCRP substrate but does not bind to OCT1
31
2
1
3
2
1
4
3 4
32
 the third VEGFR inhibitor used in the treatment of thyroid cancer
 RCC therapy, cabozantinib has been called “the most efficacious TKI” in both previously treated
and treatment naïve patients （初始治療或未接受過化療的病人）
 Adverse effects can be severe, prompting dose reduction and/or discontinuation.

 boxed warning relative to GI perforations胃腸道穿孔(3%) and fistulas瘻管(1%), as well as the potential for
severe/fatal hemorrhage (3%) 體表上皮細胞與內臟或深層組織
間形成的病理性管道
 All metabolites are inactive.

 amide cleavage, O-dealkylation, and sulfate conjugation
 Coadministration of 3A4 inhibitors or inducers should be avoided.
 Solubility drops with increasing pH, concomitant administration of PPIs may result in
compromised oral absorption
33
 a potent VEGFR inhibitor with approximately 10 times the
affinity of other TKIs for this kinase
 second-line therapy in RCC patients who have failed on
at least one systemic antineoplastic regimen Phase I: S‐oxidation
 does not inhibit CYP enzymes
 substrate for P-gp, BCRP, and organic anion transporting
protein 1B1 (OATP1B1)
Phase II: Glucuronide conjugation
34
 postsurgical therapy in RCC patients, in metastatic/advanced pancreatic neuroendocrine tumors胰臟神
經內分泌腫瘤, and in the treatment of imatinib-resistant GIST
 GIST is another highly vascularized neoplasm where sunitinib has shown clinical benefit. In patients resistant to
imatinib (the “gold standard” therapy), sunitinib enhances PSF (無進展生存期; progression-free survival) , particularly
in patients harboring exon 9 KIT mutations. is a predictive biomarker for use of imatinib,
sunitinib, regorafenib, and sorafenib in patients
• 胃腸道基質細胞瘤（GIST）：為胃腸道最常見的「非上皮」的腫瘤，僅佔所有胃腸道癌症的1%，大部分發生於中老年
人（60～70歲），一般認為GIST是由胃腸壁間質層Cajal細胞（ICC）或由幹細胞發生，ICC細胞常被稱為胃腸道調節器，
調控腸壁自主神經和平滑肌間的協調，使腸道正常蠕動。
• the “gold standard” therapy: the best standard so far among the types of therapy available.

 CYP3A4 deethylates sunitinib to an equally active secondary amine metabolite
 Appropriate precautions related to coadministration of strong CYP3A4 inhibitors or inducers should be

taken.
 The highly conjugated structure imparts a yellow color to the drug and its metabolites, which can be transferred
to skin and body fluids.
35
 first-line therapy in the treatment of RCC

 inhibits multiple kinases, including PDGFR and c-kit, but it has the highest affinity for VEGFR
 Soft tissue sarcoma is a rare and commonly fatal cancer traditionally treated with anthracycline-
based chemotherapy regimens.
 Pazopanib oral and safer alternative to patients who have failed on, or are unable to tolerate, these more toxic
agents
 Of the 7 known metabolites, only hydroxypazopanib is active

 predominantly excreted unchanged.
 P-gp and BCRP substrate
 The boxed warning of severe hepatotoxicity is shared with sunitinib and regorafenib, and
coadministration with the lipophilic antihyperlipidemic agent simvastatin significantly elevates the
hepatotoxicity marker alanine transaminase (ALT)
36
 Regorafenib and its nonfluorinated analogue sorafenib share only one
indication; hepatocellular carcinoma (肝細胞癌; HCC)
1
 second-line therapy in imatinib-resistant GIST that has progressed on sunitinib,
2
the only other VEGFR kinase inhibitor with this indication
 boxed warning for potentially fatal hepatotoxicity, regorafenib appears to be

well-tolerated by most patients
 in colorectal cancer is reserved for patients who have not responded

to a variety of first- and second-line therapies
 CYP3A4 substrate
1 2
 the pyridine N-oxide is the most predominant active metabolite after a single
dose of drug
1
2 1
 the N-demethylated N-oxide also has activity comparable to the parent drug
37

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本教材僅供授課使用，所有引用圖，表與內文，均僅用於教學

表皮生長因子受體（EGFR, epidermal growth factor receptor, HER1）

人類表皮生長因子受體2（Human Epidermal Growth Factor Receptor 2）

 contain a 4-anilinoquinazoline pharmacophore with an

that extend out into the aqueous environment.

of vandetanib (piperidine), afatinib, and neratinib (dimethylamine).

 the p-position is blocked by halogen can undergo

 p-bromo group of vandetanib is stable in vivo (p.9). afatinib

 Combine with the DNA polymerase inhibitor gemcitabine as first-line therapy in

 Cigarette smoking induces CYP1A1 (p.13)

 induces aberrant eyelash growth which can induce eye pain

 Lapatinib inhibits P-gp and BCRP (breast cancer resistance protein)

 combined with the pyrimidine antagonist capecitabine or the aromatase

inhibitor letrozole in HER2+ breast cancer patients (25%-30%) failed on first-line

 HER2 overexpression in breast cancer is associated with poor prognosis and

 CYP3A4-catalyzed dealkylation of the m-fluorobenzyl moiety sets the metabolic

stage for oxidation to the hepatotoxic quinoneimine.

 active N-demethylated metabolite

 inactivating FMO (Flavin mono-oxygenase)-catalyzed N-oxdation.

within a year’s time.

respectively) to irreversibly inactivate the kinase

 increase OS 整體存活率(Overall survival) in squamous鱗狀細胞癌NSCLC compared to erlotinib

manifestation of the drug-resistant T790M mutation

 substrate and mild inhibitor of P-gp and BCRP

 therapeutic indication is similar to lapatinib (HER2+ breast cancer in patients

 25%-30% of breast cancer patients will experience disease recurrence within

 no cross resistance with the MAb and coadministration can be beneficial

 N-oxides of the pyridine (M3)

 monodesmethyl secondary amine (M6).

 M7 is the metabolite generated by FMO.

 an acrylamide-containing third-generation irreversible TKI

 therapeutic efficacy in T790M positive NSCLC

血管內皮細胞生長因子受體 Vascular Endothelial Growth Factor Receptor

 Three VEGFR isoforms bind the angiogenesis-promoting VEGF protein,

intracellular delivery of chemotherapeutic agents

ATP-binding hinge region

ATP-binding hinge region

 Geometric isomerism is important to the TKI activity of sunitinib

 marketed in its pure eutomeric (Z) form

 Only the E isomer of axitinib is marketed

indicated for use in advanced renal cell carcinoma (RCC)晚期腎細胞癌

 the first TKI approved to treat metastatic RCC

 CYP3A4 inducers and inhibitors should not be coadministered if at all possible

 CYP3A4 oxidizes sorafenib to a similarly active N-oxide metabolite

 inhibits tumor growth through its antiangiogenic action

patients coadministered inhibitors or inducers of these proteins

 BCRP substrate but does not bind to OCT1

 Adverse effects can be severe, prompting dose reduction and/or discontinuation.

 All metabolites are inactive.

 Coadministration of 3A4 inhibitors or inducers should be avoided.

 a potent VEGFR inhibitor with approximately 10 times the

affinity of other TKIs for this kinase

 second-line therapy in RCC patients who have failed on

at least one systemic antineoplastic regimen Phase I: S‐oxidation

 does not inhibit CYP enzymes

 substrate for P-gp, BCRP, and organic anion transporting

protein 1B1 (OATP1B1)

• the “gold standard” therapy: the best standard so far among the types of therapy available.

 Appropriate precautions related to coadministration of strong CYP3A4 inhibitors or inducers should be

 first-line therapy in the treatment of RCC

 Of the 7 known metabolites, only hydroxypazopanib is active

 P-gp and BCRP substrate

 boxed warning for potentially fatal hepatotoxicity, regorafenib appears to be