REVIEWS

Flying under the radar: the new wave

of BCR–ABL inhibitors
Alfonso Quintás-Cardama, Hagop Kantarjian and Jorge Cortes
Abstract | The introduction of the BCR–ABL kinase inhibitor imatinib mesylate (Gleevec;
Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most
patients with CML receiving imatinib still harbour molecular residual disease and some
develop resistance associated with ABL kinase domain mutations. The second-generation
BCR–ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol–Myers Squibb)
have shown significant activity after imatinib failure in clinical trials, but still face similar
obstacles to imatinib, including negligible activity against the frequent BCR–ABL T315I
mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts,
in part aided by structural studies of the ABL kinase–imatinib complex have resulted in the
synthesis of a new generation of BCR–ABL inhibitors, some of which have shown encouraging
preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these
emerging therapies, which have the potential to improve the outcome of patients with CML.

Chronic myeloid leukaemia (or chronic myelogenous
leukaemia; CML), which is characterized by increased
and unregulated proliferation of predominantly myeloid
cells in the bone marrow, occurs most commonly in the
middle-aged and elderly and accounts for 15–20% of all
cases of adult leukaemia in Western populations. The
underlying cause of CML is a characteristic reciprocal
translocation between chromosomes 9 and 22, which
cytogenetically results in the Philadelphia chromo-
some (Ph) and molecularly gives rise to the chimeric
BCR–ABL1 gene1,2. In CML, the protein product of this
hybrid gene is a 210 kDa constitutively active protein
kinase containing 902 or 927 amino acids of BCR fused
to exons 2–11 of ABL1,2. In addition, the BCR–ABL1
transcript is present in approximately 25% of patients
with B‑cell acute lymphoblastic leukaemia (B-ALL). Of
these patients with B-ALL, two-thirds express a splic-
ing variant of BCR–ABL1 that gives rise to a 190-kDa
Department of Leukemia, BCR–ABL protein, whereas the remaining patients
Unit 428, The University express a 210-kDa product. It has been suggested that
of Texas M. D. Anderson
patients with CML carrying p190BCR–ABL1 may have a
Cancer Center, 1515
Holcombe Blvd, Houston, worse prognosis than those expressing the classical
Texas 77030, USA. p210BCR–ABL1 isoform3.
Correspondence to A.Q.-C. BCR–ABL kinase drives the pathogenesis of BCR–
e‑mail: ABL1-positive leukaemia through the phosphorylation
aquintas@mdanderson.org
doi:10.1038/nrd2324
and activation of a broad range of downstream substrates
Published online 14 that play critical roles in cellular signal transduction and
September 2007 transformation, and thus represent potential therapeutic
targets (FIG. 1). In this respect, the remarkable clinical
success of the ABL tyrosine kinase inhibitor (TKI)4,5
imatinib mesylate (formerly STI571 or CGP 5148B;
Gleevec, Novartis) in the treatment of patients with
CML has highlighted the potential of molecularly tar-
geted anticancer therapies, and has sparked the exten-
sive development and use of such agents in cancers in
general6,7.
Protein kinases such as ABL have evolved highly
specialized mechanisms for transitioning between
active and inactive states, and crystal structures of inac-
tive kinases have revealed a remarkable plasticity in
the kinase domain, facilitating the adoption of distinct
conformations8. Imatinib, a 2‑phenylaminopyrimidine
derivative, binds to the activation loop of ABL kinase
outside of a highly conserved ATP binding site, which
traps the kinase in an inactive conformation9. In doing
so, imatinib inhibits activity of the kinase and induces a
complete cytogenetic response (CCyR) in more than 80%
of patients with CML in chronic phase10. Noteworthy are
the annual rates of disease progression to the acceler-
ated or blastic phases among patients in chronic phase
after 5 years of follow-up — being 1.5%, 2.8%, 1.6%,
0.9% and 0.6% over the respective years10. However, the
initial optimism following these results was tempered by
the realization that the majority of patients with CML
receiving imatinib retain residual leukaemic cells that
were detectable by molecular techniques10, and that any

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© 2007 Nature Publishing Group
 REVIEWS

to which imatinib binds9,13,18,19. The impaired interaction

between imatinib and ABL kinase as a consequence of
Y177 mutations within the ABL kinase is best exemplified by
the T315I mutation, which has frequently been detected
BCR ABL in patients with imatinib-resistant CML20, but also in
some patients with imatinib-naive CML13. This threo-
GRB2 P
P
nine residue at position 315, also called the gatekeeper,
STAT
SOS GAB2 is located near the ABL catalytic domain in the centre
of the imatinib binding site, which controls access to a
RAS SFK hydrophobic region of the enzymatic active site. Different
?
(HCK, LYN) BCR–ABL mutants have been associated with differ-
SHP2 PI3K
ent degrees of fitness (oncogenicity) relative to that of
JNK wild-type BCR–ABL. Gain-of-fitness has been shown to
P
AKT ICSBP correlate with increased kinase activity of the enzyme
and enhanced transformation potential. A notable excep-
JUN
tion is the T315I mutation, which displays enhanced
oncogenicity despite reduced kinase activity for classi-
cal ABL substrates21. Using mass-spectrometry-based
phosphotyrosine profiling techniques, it has been shown
BCL2 STAT5 that T315I is associated with a specific phosphorylation
BCLX
pattern in the phosphate binding loop of BCR–ABL21.
Nucleus This might explain the distinct oncogenic potential of
Figure 1 | Oncogenic signalling of BCR–ABL kinase. This highly simplified scheme T315I relative to wild-type BCR–ABL and the closely
illustrates some of the more important BCR–ABL signalling pathways. Phosphorylation at related T315A mutation, which at the same time unveils
Nature
the Y177 residue of BCR generates a high-affinity docking site Reviews | Drug Discovery a previously unknown role of T315I in substrate recog-
for growth-factor
receptor-bound protein 2 (GRB2), which in turn binds the scaffolding adaptor GRB2- nition21. Mutations at other positions within the ABL
associated binding protein 2 (GAB2), as well as SOS (a guanine-nucleotide exchanger of kinase other than T315I weaken the binding of imatinib
RAS), resulting in RAS–MAPK activation (leading to BCL2 gene transcription). to various degrees, which in some cases is enough to
On phosphorylation by BCR–ABL, GAB2 recruits SHP2 (also known as PTPN11) and phos- confer clinical resistance.
phatidylinositol-3 kinase (PI3K), which leads to AKT activation. BCR–ABL also activates
The T315I mutation poses a formidable therapeutic
other signalling pathways such as signal transducer and activator of transcription 5
(STAT5), leading to BCLX gene (also known as BCL2L1) transcription and the SRC family
challenge as not only does it mediate complete resist-
kinases (SFKs) LYN and HCK. By contrast, BCR–ABL represses interferon consensus ance to imatinib, but also to many of the next generation
sequence binding protein (ICSBP) transcription through an unknown mechanism, which of ABL kinase inhibitors, including dasatinib (Sprycel;
releases the ISCBP-mediated inhibition of BCL2 and BCLX gene transcription. Notably, Bristol–Myers Squibb) and the imatinib-related com-
downregulation of ICSBP transcripts has been consistently documented in patients with pound nilotinib (Tasigna; Novartis). Although less
chronic myeloid leukaemia (CML). So, the net effect of BCR–ABL kinase activation is the frequent than ABL kinase domain mutations, other
promotion of cell proliferation and survival through activation of the RAS, SHP2 and mechanisms linked to ABL TKI resistance have been
PI3K–AKT signalling pathways that lead to increased BCL2 and BCLX expression and identified in vivo, such as BCR–ABL1 gene amplifica-
inhibition of ICSBP transcription. Small molecules targeting BCR–ABL kinase represent tion, overexpression of the BCR–ABL protein, activa-
the current mainstay of CML therapy. Pointed arrows indicate direct interactions and/or
tion of SRC family kinases (SFKs) 17,22 and transporters
activations. Blunt-ended arrows indicate inhibitory effects. P, phosphate.
involved in drug efflux, suggesting that targeting this
group of proteins could be a useful characteristic for
agents to treat CML.
response observed in patients in the more advanced The need for new strategies to treat imatinib-resistant
stages of CML (accelerated and blastic phases) are CML has stimulated considerable efforts to develop novel
typically short-lived11. Moreover, patients treated with BCR–ABL inhibitors. Two such agents — dasatinib and
imatinib may eventually develop resistance, particularly nilotinib — have already demonstrated success against
those treated in the accelerated or blastic phases. imatinib-resistant CML in clinical trials. Furthermore,
A pervading theme regarding resistance to ABL TKI propelled by advances in structural biology that have
therapy in CML is the development of point mutations aided rational inhibitor design (BOX 1), a plethora of
within the kinase domain of BCR–ABL1. The frequency novel compounds have proved highly active against
of BCR–ABL1 mutations in imatinib-resistant patients the BCR–ABL protein kinase in preclinical studies,
ranges from 40–90% depending on the CML phase and and some have already shown promising results in pre-
the methodology of detection and definition of resist- liminary clinical studies in patients with CML. Several
ance12–17. To date, more than 50 distinct point mutations of these agents inhibit the kinase activity of BCR–ABL
encoding single amino-acid substitutions in the kinase through mechanisms of action other than interference
domain of the BCR–ABL1 gene have been detected in with the ATP binding site of the kinase while preserving
patients with imatinib-resistant CML. At the protein their specificity for BCR–ABL. This may provide a more
level, these point mutations result in distorted configu- favourable toxicity profile in vivo and overcome mecha-
rations of the ABL kinase–imatinib interface. The result nisms of resistance to imatinib, dasatanib and nilotinib,
is that ABL is unable to adopt the inactive conformation including the T315I mutation in some cases.

nature reviews | drug discovery volume 6 | october 2007 | 835

© 2007 Nature Publishing Group
REVIEWS
Box 1 | Rational design of kinase inhibitors
Protein kinases are molecular switches that have evolved highly specialized
conformational plasticity for transitioning between inactive and active states.
The protein kinase complement of the human genome (that is, kinome) encompasses
more than 500 protein kinases. Several members of the serine/threonine and the
tyrosine family of protein kinases play crucial roles in cancer. To date, 90 genes
encoding tyrosine kinases have been identified, of which 58 encode receptors and
32 encode non-receptor tyrosine kinases123. Many, albeit not all, protein tyrosine
kinases are involved in cellular-signalling pathways — the deregulation of which has
been implicated in the development of tumorigenesis124.
The highly conserved kinase domain of protein kinases consists of a bi-lobed
structure in which Mg-ATP is located in a deep cleft between the N‑terminal and
C‑terminal lobes125. Most tyrosine kinase inhibitors (TKIs) have been designed to target
the ATP binding site of the kinase in the active conformation. TKIs acting in this manner
have been termed type I kinase inhibitors. By contrast, type II kinase inhibitors bind
preferentially to an inactive conformation of the kinase, locking it in that state and
preventing its activation125. In addition to the ATP binding cleft, type II inhibitors bind
an adjacent hydrophobic pocket created by the activation loop, in which the
phenylalanine of the conserved motif DFG (Asp-Phe-Gly) swings more than 10 Å away
from its position (DFG-out) in the kinase active conformation125,126. TKIs targeting this
hydrophobic pocket (for example, imatinib, BIRB‑796) bind a group of amino acids that
are less conserved than those surrounding the ATP binding site, which has been
proposed as an ideal target for the design of highly selective type II TKIs (FIG. 3). This
concept of high TKI selectivity is further supported by the fact that many kinases
cannot adopt an inactive conformation128. The DFG-out conformation has been solved
crystallographically for a select group of kinases, including ABL; mast/stem-cell growth
factor receptor (KIT); Aurora A (AURKA; also known as STK6); epidermal growth-
factor receptor (EGFR); p38 (also known as MAPK14); KDR; and BRAF125. So, type II
TKIs rationally designed in this manner could have high affinity with a restricted
spectrum of inhibitory activity against various oncogenic protein kinases expressed in
haematological malignancies and solid tumours.
An alternative approach to obtain highly selective TKIs, which may be used when
the cancer (for example, chronic myeloid leukaemia) is resistant to ATP-competitive
compounds, is to synthesize compounds with affinity for binding sites that,
although physically distant from the ATP binding site, regulate the kinase activity127.
A prime example of such an approach is the development of ‘substrate competitive’
compounds that block the binding of the kinase to its substrate, thereby preventing
substrate phosphorylation (FIG. 3).
With the excitement generated by the success of
dasatinib and nilotinib, many of these new agents have
been ‘flying under the radar screen’. In this article, we
summarize these recent advances in the discovery and
development of kinase inhibitors for CML, and discuss
the potential of these agents as a more effective treat-
ment for CML. Ideally, the clinical development and full
approval of these agents should be expedited by the suc-
cess of their immediate predecessors so that they could
become available to patients who may benefit from their
use and to researchers to continue their endeavours on
the ever more realistic enterprise of curing CML.
The second generation of BCR–ABL inhibitors
The second-generation BCR–ABL inhibitors nilotinib
and dasatinib have proved highly efficacious in patients
with CML following failure of imatinib therapy 23–30
(TABLE 1). Both agents have demonstrated remarkable
activity against most imatinib-resistant ABL mutants,
except for the T315I mutation24,25,31,32.
Nilotinib is a phenylaminopyrimidine derivative
developed by the reconciliation of the crystal structures
of imatinib and ABL kinase in a complex32. Replacing
the N‑methylpiperazine ring in the imatinib molecule,
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© 2007 Nature Publishing Group
which participates in hydrogen-bond interactions with
both Ile360 and His361, increases affinity for the inac-
tive conformation of wild-type BCR–ABL by 20-fold
to 30-fold, while similar activity against mast/stem-cell
growth factor receptor (KIT; IC50 of 60 nM) and platelet-
derived growth factor receptor (PDGFR; IC50 of 57 nM)
is maintained32.
Dasatinib is a multikinase inhibitor with potent activ-
ity against BCR–ABL kinase (IC50 <1 nM) and SFKs (IC50
of 0.2–1.1 nM)31 that has been approved by the US Food
and Drug Administration (FDA) for the treatment of
patients with CML following failure or with intolerance
to imatinib therapy. Unlike other ABL or SFK inhibitors,
dasatinib was originally designed as an immunosuppres-
sant. A potentially advantageous feature of dasatinib
over imatinib and nilotinib is its ability to bind ABL
with greater affinity, due, at least in part, to it recogniz-
ing multiple states of the enzyme25,31,33. The resolution
of the co-crystal structure of dasatinib in complex with
the active conformation of ABL appears to support this
hypothesis34,35. As a result, the number of BCR–ABL1
mutants that confer resistance to dasatinib is limited
almost exclusively to direct contact sites20,36.
A potential limitation of these compounds, par-
ticularly of dasatinib, is that their increased potency
may be associated with untoward off-target toxicities,
which probably relate to their inhibitory activity against
a broader range of protein kinases than imatinib. For
instance, dasatinib, in addition to inhibiting SFKs in the
subnanomolar range, is also a potent inhibitor of the
KIT, PDGFR and ephrin receptor (EPHA2) tyrosine
kinases, which are directly implicated in haematopoi-
esis, control of tissue interstitial-fluid pressure and ang-
iogenesis. These effects may provide the physiological
explanation for some of the toxicities associated with
dasatinib therapy, such as myelosuppression and pleural
effusion. However, dasatinib-mediated SFK inhibition
might be beneficial in cases of imatinib-resistant CML
that are due to overexpression of SFKs such as LYN22, as
well as in Ph-positive B-ALL in which SFKs seem to play
an important pathogenetic role.
Recently, imatinib-mediated ABL kinase inhibi-
tion has been linked to the potential development of
cardiotoxicity in patients with CML37. This contention
has been supported by experimental models in which
imatinib-treated mice develop left-ventricular contrac-
tile dysfunction. This toxic myopathy appears second-
ary to imatinib-induced activation of the endoplasmic
reticulum stress response and cell death37. Although only
12 out of 1,995 (0.6%) patients with CML treated with
imatinib in six clinical trials developed congestive heart
failure possibly related to imatinib exposure38, patients
receiving therapy with the highly potent ABL kinase
inhibitors nilotinib and dasatinib must be monitored
for this complication.
Therapeutic targeting of SFKs in CML
The SFKs comprise nine cytoplasmic structurally
homologous non-receptor intracellular tyrosine kinases
(SRC, FYN, YES, BLK, YRK, FGR, HCK, LCK and
LYN)39. Some SFKs are ubiquitously expressed, whereas
 REVIEWS

Table 1 | Haematological and cytogenetic responses to nilotinib and dasatinib* LYN and FGR — the three main SFKs expressed in early
haematopoetic progenitor and myeloid cells — can
ABL- CML No. Response rate (%) Refs efficiently induce a CML-like myeloproliferative disor-
kinase phase patients
CHR Cytogenetic der43. Second, mice with CML-like disease responded
inhibitor
Major Complete to imatinib but not treatment with CGP76030, a TKI
that inhibits all SFKs, suggesting that SFKs other than
Nilotinib Chronic 316 74 52 34 28
HCK, LYN and FGR do not compensate for the lack
Accelerated 64 23 36 22 29 of activity of these three. However, HCK, LYN and
Blastic and 161 28 NR NR 30 FGR are required for BCR–ABL1-induced B‑ALL.
Ph+ ALL (120+41) Overall, these results suggest that BCR–ABL kinase
Dasatinib Chronic 387 90 52 39 26 uses different signalling pathways to induce CML and
Accelerated 107 39 33 24 23 BCR–ABL1-positive B‑ALL43.
Patients with the BCR–ABL1 T315I mutation are
Blastic 116 26 38 33 27 resistant to the potent ABL and SFK inhibitor dasatinib,
(myeloid)
which suggests that pure SFK inhibition will have neg-
Blastic 46 33 57 54 27 ligible therapeutic activity in most CML cases. Further
(lymphoid)
supporting this hypothesis is the fact that patients
*These are results of Phase II studies of patients with Philadelphia chromosome (Ph)-positive with CML who relapse during dasatinib therapy usu-
leukaemia resistant or intolerant to imatinib therapy. ALL, acute lymphoblastic leukaemia;
CHR, complete haematological response (normalization of peripheral blood counts and ally express dasatinib-resistant BCR–ABL1 mutations.
disappearance of all signs and symptoms related to leukaemia for at least 4 weeks); complete However, overexpression and/or activation of the SFKs
cytogenetic response, 0% Ph-positive cells; CML, chronic myeloid leukaemia; major cytogenetic
response, 0–35% Ph-positive cells; NR, not reported.
HCK and LYN has been implicated in some cases of
CML progression to blast phase and imatinib resist-
ance22,49–51. Although these results point towards a causa-
others display tissue-specific expression patterns 39. tive role of SFKs in BCR–ABL-independent resistance,
Importantly, the SFKs LCK and FYN are linked with the it remains unknown whether the concomitant inhibi-
co-receptors CD4 and CD8 and have a crucial role in tion of BCR–ABL and SFKs with dasatinib will lead to
mediating T-cell-receptor signal transduction in clonal improved responses in patients overexpressing SFKs.
lymphocytes40. Moreover, it has been shown that HCK phosphorylates
Experiments with SRC-dominant-negative mutants the activation loop of ABL kinase in vitro and blocks the
suggest that SFKs are involved in the proliferation binding of imatinib9.
of BCR–ABL1-expressing cell lines39,41,42. BCR–ABL The kinase domain of ABL can readily adopt a
kinase activates the SFKs LYN, HCK and FGR43. In conformation that closely resembles that of the inac-
fact, multiple domains of BCR–ABL have been shown tive SFKs52 (FIG. 2). Not surprisingly, ATP-competitive
to interact with HCK and LYN, leading to their activa- compounds originally developed as SFK inhibitors
tion. The formation of the HCK–BCR–ABL complex frequently exert potent inhibition of ABL kinase owing
alone appears to be sufficient for activation of SFKs, to the striking resemblance between the catalytically
with neither process being dependent on the activity of active state of both protein kinases18,53. This similarity,
ABL kinase44,45. This is supported by the fact that SFKs and the important role of SFKs in BCR–ABL signalling
remain active following imatinib inhibition of BCR–ABL and imatinib-resistance, has led to the development of
kinase activity in leukaemic cells. SFK activation may an array of small-molecule TKIs with overlapping activ-
promote phosphorylation of the Tyr177 binding site for ity against both ABL and SFKs and enhanced activity
growth-factor receptor-bound protein 2 (GRB2) in the against imatinib-resistant BCR–ABL kinase mutant
BCR moiety of BCR–ABL42,44. GRB2 recruits the linker isoforms (TABLE 2).
protein GRB2-associated binding protein 2 (GAB2), as
well as SOS, a guanine-nucleotide exchanger of RAS. Dual ABL and SFK inhibitors
The complex BCR–ABL–GRB2–SOS promotes RAS– Bosutinib. Bosutinib (also known as SKI 606) is an
mitogen-activated protein kinase (MAPK) activation, orally available 4‑anilino‑3-quinolinecarbonitrile deriv-
which results in BCL2 gene transcription. Importantly, ative54 that has potent dual SFK and ABL tyrosine kinase
BCR–ABL-induced GAB2 phosphorylation facilitates inhibitory activity55. Bosutinib has demonstrated potent
SHP2 (also known as PTPN11) recruitment and activa- antiproliferative activity against three BCR–ABL1-posi-
tion of the phosphatidylinositol-3 kinase (PI3K)/AKT tive cell lines, including LAMA84R, in which resistance
pathway. On activation, HCK activates signal transducer is caused by BCR–ABL1 gene amplification, and K562R
and activator of transcription 5 (STAT5), which in turn and KCL22R, in which the underlying mechanism of
modulates gene transcription by binding to cognate resistance has not yet been defined55. Furthermore,
DNA sequences43,46 (FIG. 1). HCK-mediated STAT5 acti- bosutinib proved active in vitro against cells transfected
vation leads to upregulation of the expression of cyclin with wild-type BCR–ABL1 and several clinically impor-
D1, which results in the cell-cycle progression from G1 tant mutant isoforms, except for T315I55 (TABLE 2). The
to S phase47,48. in vivo activity of bosutinib was demonstrated in human
A role for SFKs in the pathogenesis of CML has been KU812 xenografts in nude mice and in syngeneic
challenged by recent findings. First, transduction of BCR–ABL1 wild-type and mutant Ba/F3 xenografts55.
BCR–ABL1 into bone marrow from mice lacking HCK, In contrast to imatinib and dasatinib, bosutinib exerts

nature reviews | drug discovery volume 6 | october 2007 | 837

© 2007 Nature Publishing Group
REVIEWS

a activity of bosutinib has been explored in a Phase I/II

SRC kinase family Core P SRC, YES, FYN, study involving 18 patients with CML in chronic phase
SH3 SH2 Kinase domain LYN, LCK, BLK, who were resistant or intolerant to imatinib57. Bosutinib
Phosphorylated tail HCK, FGR, YRK was given as a single dose at 400 mg (n = 3), 500 mg
Myristate/palmitate
(n = 3) or 600 mg (n = 12) daily. Side effects were mini-
mal with the most frequent being mild to moderate
ABL kinase family
diarrhoea (87%), nausea (33%) and vomiting (20%). In
1b contrast to dasatinib58, no pleural effusion or pulmo-
Myristate SH3 SH2 Kinase domain ABL, ARG nary oedema was observed with bosutinib and these
1a Last exon region events have been rarely reported with either imatinib
or nilotinib59, perhaps as a result of the minor activity
BCR SH3 SH2 Kinase domain BCR–ABL of these agents against PDGFR55. The extent of PDGFR
inhibition may play a crucial role in the development of
pleural effusion, as this occurrence has been reported
b ABL kinase SH2–kinase more frequently in patients receiving higher dasatinib
linker Kinase
domain doses on a twice-daily schedule60. The dose-limiting
SH3 toxicity of bosutinib occurred at 600 mg daily in the
domain
form of severe rash. Of the seven patients who received
bosutinib for more than 12 weeks, three had CCyRs and
PD166326
H2N P-loop one had minimal cytogenetic response. Responders har-
Y412
boured various BCR–ABL1 mutations, but no patient
SH3–SH2 with the T315I mutation responded. A dose of 500 mg
connector Activation daily was selected as the dose for the Phase II portion
loop of the study, which is currently recruiting patients in all
phases of CML and BCR–ABL1-positive B‑ALL57. On
the basis of these results, bosutinib is currently being
tested in patients with CML who have become resistant
SH2 to imatinib or the second-generation TKIs nilotinib and
domain Myristoyl group
α-helix dasatinib.
COOH
Figure 2 | Structural organization of BCR–ABL and SFKs. SRC family kinases (SFKs) INNO‑406. INNO‑406 (also known as NS-187) (TABLE 2)
regulate signal transduction pathways involved in cell growth, differentiation and is a 3‑substituted benzamide derivative obtained through
survival. a | The common central core of SFKs and BCR–ABLNature Reviewsof| Drug
is composed Discovery
a tyrosine the introduction of various hydrophobic substituents at
kinase or SRC-homology 1 (SH1) domain, which is preceded by an SH2 domain and an
the phenyl ring adjacent to the piperazinylmethyl group
SH3 domain. These three domains are conserved in terms of their sequence homology
(42% between ABL and SRC) and arrangement129. By contrast, regions upstream of the
of imatinib61. INNO‑406 is a dual-specificity ABL and
SH3 domain and downstream of the kinase domain are variable. The NH2-terminus in the LYN kinase inhibitor that is 25–55-times more potent
ABL family of kinases is the ‘Cap’ region, which is present in different splice variants. The than imatinib62 against ABL. In addition, INNO‑406
homology region in SFK is the N‑terminal membrane-localization domain (also referred inhibited the in vitro growth of cells producing a wide
to as the SH4 domain), which anchors the protein to membranes through myristoyl and/ range of mutant BCR–ABL oncoproteins63, and pro-
or palmitoyl groups. b | A ribbon representation of the ABL kinase in complex with the longed the survival of Balb/c nu/nu mice engrafted with
ABL and SFK inhibitor PD166326 (Ref. 53). The catalytically active state of ABL kinase BaF3/E255K, Y253F, G250E, Q252H, M351T or H396P
closely resembles the active form of SFKs and is often potently inhibited by ATP- mutant cells62, but not with T315I62,63. INNO‑406 inhib-
competitive molecules originally developed as SFK inhibitors. Dual ABL and SFK ited 4 out of the 79 tyrosine kinases tested, including
inhibitors have proved active against chronic myeloid leukaemia cells exhibiting various
ABL, ABL-related gene (ARG; also known as ABL2) and
forms of imatinib resistance, including BCR–ABL1 overexpression, SFK activation and
several BCR–ABL kinase domain mutations.
FYN, but not PDGFRα/β, SRC, BLK or YES at 0.1 µM,
a concentration that adequately inhibits ABL kinase62.
Furthermore, INNO‑406 potently inhibited LYN kinase
(IC50 of 19 nM), which has been implicated in BCR–ABL-
no significant inhibition of KIT or PDGFR, which may independent resistance22, and so INNO-406 might have
result in a safer toxicity profile in vivo55. The superior further potential in imatinib-resistant CML62.
spectrum of activity of bosutinib with respect to imat- Like imatinib, INNO‑406 is a substrate of
inib may be attributed to its ability to bind both inac- P‑glycoprotein61. As a result, the concentration of both
tive and intermediate conformations of BCR–ABL 55. agents in the CNS is approximately 10% of that detected
Importantly, bosutinib is significantly more potent than in plasma64–67. However, unlike imatinib, in a mouse
imatinib in inhibiting BCR–ABL tyrosine kinase in both model of Ph-positive CNS leukaemia, this concentra-
primitive and committed CD34 +CD38– progenitors tion of INNO‑406 is sufficient to inhibit the growth of
from untreated CML patients. Unlike imatinib, bosuti- BCR–ABL1-positive leukaemic cells producing wild-
nib therapy did not result in a compensatory increase in type as well as multiple BCR–ABL1 mutant isoforms,
the important BCR–ABL downstream effector p42/44 except for T315I. Cyclosporine A, a P‑glycoprotein
MAPK, which could potentially be beneficial in target- inhibitor, administered before INNO‑406 signifi-
ing malignant stem cells56. The preliminary clinical cantly enhanced the influx of this TKI into the CNS,

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Table 2 | Imatinib compared with a selection of promising dual ABL/SFK inhibitors in clinical and preclinical development*
Compound Chemical structure Chemical Potency against Potency Comments Refs
class BCR–ABL against
SFKs
Imatinib H H N 2-phenyl- • Inhibits p210 IC50 > • Standard therapy 5
(Gleevec; N N N N
amino- BCR–ABL1-positive 100 mM for patients newly
Novartis) pyrimidine 32D and MO7e cells diagnosed with
N O with IC50 ~300 nM CML based on
Phase III data

Bosutinib Cl Cl 4-anilino-3- • Inhibits WT, Y253F IC50 < • DLT in Phase I 54–57
quinoline- and D276G BCR– 10 nM studies occurred
HN O
carbonitrile ABL1 mutants with at 600 mg daily
derivative IC50 values of 13–40 • Undergoing
O CN
nM and E255K with Phase II studies
IC50 of 394 nM in CML after
N O N • Not active against imatinib failure
N T315I

INNO-406 CF3 Benzamide • Potent inhibitor IC50 of 19 • Reaches 61–64

derivative of WT BCR–ABL nM against concentrations
H H N N (IC50 of 5.8 nM) LYN kinase in CSF enough to
N N N and a wide array but no inhibit multiple
of mutants, except activity BCR–ABL1
N O T315I against mutants
• Active against the BLK, SRC • Undergoing
WT BCR–ABL1- or YES clinical evaluation
positive K562 in Phase I studies
N N
(IC50of 11 nM) and
293T (IC50 of 22 nM)
cell lines
AZD0530 O Anilino- • IC50 of 30 nM in IC50 of 1–5 • Highly selective, 70,71
O quinazoline kinase-based assays nM; active orally bioavailable
O derivative • IC50 of 220 nM in in a SRC- • Unknown activity
H human K562 cells transfected against BCR–ABL1
O N
expressing WT NIH3T3 mutants
N N
Cl BCR–ABL1 tumour • Evaluated in Phase I
xenograft studies in healthy
N
O N in athymic volunteers
mice • DLTs: diarrhoea
and vomiting
*Continued in TABLE 3. IC50, concentration of an inhibitor required for 50% inhibition of its target; CML, chronic myeloid leukaemia; CSF, cerebrospinal fluid;
DLT, dose-limiting toxicity; SFKs, SRC family kinases; WT, wild-type.

resulting in improved activity against Ph-positive
leukaemic cells in vivo64. Approximately 6% of adult
patients in lymphoid blast phase CML have evidence
of CNS involvement. However, this incidence is close
to 12% in patients with BCR–ABL1-positive leukaemia
who relapse during imatinib monotherapy68. In view of
the scarce data available regarding the actual concentra-
tions of nilotinib or dasatinib in the CNS at the dose
schedules currently used in clinical practice, INNO‑406
represents a promising alternative for the treatment
of CNS BCR–ABL1-positive leukaemia. In a Phase I
study, 11 patients with CML (8 in chronic phase, 2 in
accelerated phase and 1 in blast phase), and 3 patients
with BCR–ABL1-positive ALL, who had failed prior
imatinib therapy, received INNO‑406 after imatinib
failure at doses ranging between 30 mg and 240 mg
daily69. INNO‑406 was well-tolerated. Three out of six
patients — two in chronic phase and one in accelerated
phase — who received INNO‑406 for more than 4 weeks
have evidence of clinical response. Dose escalation is
ongoing to identify a recommended Phase II dose.
AZD0530. AZD0530 (TABLE 2) is a TKI obtained from a
novel series of anilinoquinazolines substituted at the C5
position of the quinazoline ring, which imparts excellent
selectivity towards SFKs while preserving activity against
ABL70,71. AZD0530 inhibited the cell proliferation of the
SRC-transfected mouse NIH3T3 cells with an IC50 value
of 76 nM70. This drug was well-tolerated in Phase I trials
in healthy individuals at a dose of 500 mg72. The activity
of AZD0530 against BCR–ABL1-resistant mutants has
not yet been reported.
2,6,9-trisubstituted purine derivatives. AP23464 and
its analogue AP23848 (TABLE 3) are ATP-based 2,6,9-
trisubstituted purine derivatives conceptually designed
as inhibitors of bone resorption and metastatic spread,
respectively73. Compound optimization involved an

nature reviews | drug discovery volume 6 | october 2007 | 839

© 2007 Nature Publishing Group
REVIEWS
iterative design approach using molecular docking to
an SRC model, followed by compound synthesis and
SRC-kinase inhibition assays74. Both agents are potent
ATP-competitive dual inhibitors of ABL and SFKs75.
Although both compounds bind to the active form of
SRC kinase, the affinity of AP23464 for this target is
substantially higher than that of AP23848. This differ-
ence has been attributed to the presence of the bulky
hydroxyphenethyl group located at the N9 position of
AP23464 (Ref. 73). AP23464 and AP23848 inhibit the
proliferation of BaF3 cells transformed with BCR–ABL1
with IC50 values of 13.4 nM and 5.4 nM, respectively76.
Similarly, AP23464 and AP23848 inhibit SRC kinase
with respective IC50 values of 67 nM and 0.45 nM73. The
co-crystal structure of AP23464 and SRC reveals that the
DFG (Asp-Phe-Gly) motif at the start of the activation
loop is distinctly open and catalytically favourable73. In
one study, the growth of Ba/F3 mouse pro-B-cell lines
producing either wild-type BCR–ABL1 or the commonly
observed clinical mutants Q252H, Y253F, E255K, M351T
and H396P was inhibited by AP23464 with IC50 values
ranging from 8 nM to 94 nM75, resulting in remarkable
apoptosis of Ba/F3 cells expressing wild-type or mutated
BCR–ABL1, but not parental Ba/F3 cells75. AP23464
demonstrated potent activity against multiple imatinib-
resistant BCR–ABL1 mutants76 (TABLE 3). However, pro-
liferation of parental Ba/F3 cells (IC50 >8 µM) and Ba/F3
cells expressing BCR–ABL1 T315I (IC50 >9 µM) was not
significantly inhibited by AP23464 (Ref. 75). In combina-
tion with imatinib, AP23464 suppressed drug resistance,
except for the BCR–ABL1 T315I mutation76.
Based on its preliminary favourable pharmacokinet-
ics and similar effect on haematopoietic colony forma-
tion compared with AP23464, AP23848 was selected for
in vivo testing77. Treatment of female DBA/2 mice that
had previously been injected subcutaneously with syn-
geneic P815 mouse mastocytoma cells with AP23848,
resulted in the inhibition of activation-loop mutant KIT
phosphorylation77. Although the serum concentration of
AP23848 after 1 hour of treatment was 1,117 nM, this
dropped to an average of 70 nM at 8 hours, indicating a
short plasma half-life of approximately 2 hours77. Based
on the activity of imatinib on BCR–ABL1-expressing
tumours, in which tumour regression requires continu-
ous kinase inhibition, the identification of 2,6,9-trisubsti-
tuted purine derivatives with superior pharmacokinetics
compared with AP23848 is warranted before the activ-
ity of such compounds is assessed in clinical trials in
patients with CML.
Pyrido[2,3‑d]-pyrimidines. PD166326 (TABLE 3) is the
most potent compound of a series of ATP-competitive
pyrido[2,3‑d]pyrimidine TKIs originally characterized
as inhibitors of fibroblast growth factor receptor (FGFR)
and PDGFR78. PD166326 potently inhibited K562 prolif-
eration with an IC50 of 0.3 nM79, and has a relatively long
half-life (8.4 hours) at steady state when administered
orally to Balb/c mice, suggesting that once‑a-day dosing
would be feasible in humans80. Crystallographic studies
predict that PD166326 interacts with 11 amino acids of the
BCR–ABL kinase, compared with at least 21 for imatinib,
840 | october 2007 | volume 6 www.nature.com/reviews/drugdisc
© 2007 Nature Publishing Group
which may allow PD166326 to retain activity against cer-
tain imatinib-resistant mutations18. Indeed, treatment of
syngeneic mice with PD166326 was more effective than
imatinib in controlling Ph-positive leukaemia express-
ing the imatinib-resistant BCR–ABL1 mutants H396P
and M351T80. Recently, PD166326 was shown to inhibit
multiple imatinib-resistant BCR–ABL1 mutants76, but not
T315I76,80 (TABLE 3). Furthermore, the yield of PD166326-
resistant BCR–ABL1-positive colonies in a cell-based
screen was consistently lower than that for imatinib76,81,
with the most frequently recovered mutant clones being
G250E, T315I, F317L, E355G, E255K/V and Y253H76.
The remarkable in vivo activity of PD166326 provides a
solid rationale to develop this TKI in human CML studies.
However, its limited water solubility and the development
of tubulointerstitial nephritis in several PD166326-treated
mice at autopsy at the 50 mg per kg twice-daily dose may
represent potential hurdles that may hamper the clinical
development of this promising drug80.
Other pyrido[2,3‑d]-pyrimidine dual ABL and SFK
inhibitors include PD173955 and PD180970 (TABLE 3).
PD173955 is a potent BCR–ABL kinase inhibitor with
IC50 values of 1–2 nM82. A model of PD173955 interact-
ing with both the open and closed conformations of ABL
kinase suggests that PD173955 can nestle into the ABL
binding pocket, avoiding major steric clashes with the
protein, although minor adjustments of the P‑loop are
necessary18. PD180970 potently inhibited the BCR–ABL
kinase (IC50 of 5 nM)83, inducing apoptosis of CD34-posi-
tive leukaemic cells from patients with imatinib-resistant
CML in blast phase83,84, and of cells harbouring clinically
relevant mutations84 without having any apparent effects
on cell proliferation of the BCR–ABL1-negative HL60
cell line83. However, the relative insolubility of PD180970
may hamper the clinical development of this TKI in
BCR–ABL1-positive leukaemia83.
Other dual ABL and SFK inhibitors. Two groups of
BCR–ABL kinase inhibitors have been recently identi-
fied based on a synthetic route involving the 1,3-dipolar
cycloaddition of diazoketones with activated acetylenes,
followed by heat-induced cycloreversion to yield furans,
whose planar architecture permits the drug to reach deep
within the ATP pocket without disturbing the confor-
mation of the ABL kinase domain85. Two of the most
promising compounds, the acetylanes AC22 and K1P,
inhibited the growth of 32Dtetp210 BCR–ABL cells with
IC50 values of 1 µM and also exhibited inhibitory activity
against the SFKs LYN and FYN85. Further studies will
be necessary to determine whether these compounds
may be effective in the presence of ABL kinase point
mutations.
A series of compounds initially characterized as
specific SFK inhibitors have also been shown to inhibit
ABL kinase. The pyrazolo[3,4‑d]pyrimidine derivative
PP1 inhibited SRC (IC50 of 170 nM) and HCK (IC50 of
20 nM), whereas the related compound PP2 potently
inhibited HCK (IC50 of 5 nM)86. PP1 and PP2 inhib-
ited BCR–ABL kinase phosphorylation in intact p210
BCR–ABL1-positive FDCP1 cells with an IC50 of 1 µM87.
Like PP1, the 5,7-diphenyl-pyrrolo[2,3‑d]pyrimidine
 REVIEWS

Table 3 | Imatinib compared with a selection of promising dual ABL/SFK inhibitors in clinical and preclinical development*
Compound Chemical structure Chemical Potency against Potency Comments Refs
class BCR–ABL against SFKs
AP23464 O 2,6,9- • IC50 of 13.4 nM IC50 of 67 nM • Additive/synergistic 73–76
P trisubstituted against WT with imatinib
purine BCR–ABL • Active against
HN
derivative 58 imatinib-resistant
BCR–ABL1 mutants,
N
N with IC50 values ranging
from 3 nM (E282D) to
N N 201 nM (A269V)
• Not active against
T315I
OH • In preclinical
development
AP23848 2,6,9- • IC50 of 5.4 nM IC50 of • Like AP23464, 73–76
O trisubstituted against WT 0.45 nM still in preclinical
P purine BCR–ABL development
derivative
HN

N
N

N N

OH

PD166326 Cl Pyrido[2,3- • Inhibits cell IC50 ~5 nM • Inhibits 57 imatinib- 18,76,

d]pyrimidine proliferation against resistant BCR–ABL1 78–81
N derivative of BCR–ABL1- SRC and LYN mutants, with IC50 values
positive cell line kinases ranging from 1 nm
HO Cl
N N N O K562 with IC50 (I502M) to 199 nM (L248R)
H of 0.3 nM • In preclinical development
CH3

PD173955 Cl Pyrido[2,3- • IC50 of 1–2 nM IC50 <5 nM • Binds both the active 18,82
d]pyrimidine and inactive
N derivative configurations of ABL
H3C Cl
kinase
S N N N O • In preclinical
H
CH3 development

PD180970 Cl Pyrido[2,3- • Inhibits tyrosine IC50 of 0.8 nM • Inhibits BCR–ABL1 83,84

d]pyrimidine phosphorylation against SRC E255K, A380T, H396P
F
N derivative of p210-BCR– kinase and Y253F, but not
Cl
ABL kinase in T315I
H3C N N N O K562 cells with • In preclinical
H
CH3 IC50 of 170 nM development
*Continued from TABLE 2. IC50, concentration of an inhibitor required for 50% inhibition of its target; SFKs, SRC family kinases; WT, wild-type.

derivative CGP76030 had moderate activity against ABL
kinase88. Approximately 25–50 µM of PP1 or 5–10 µM
of CGP76030 was necessary to inhibit substrate phos-
phorylation by BCR–ABL in COS7 and 32D BCR–ABL1-
positive cells88. However, PP1 and CGP76030 blocked
cell growth and survival in COS7 cells expressing
various imatinib-resistant BCR–ABL1 mutants, except
for T315I88. However, further investigation is required
to characterize the specificity and safety of these com-
pounds before they can be introduced in the clinic.
Non-ATP-competitive BCR–ABL kinase inhibitors
All TKIs currently used for the treatment of CML com-
pete with ATP for the binding site of the BCR–ABL
oncoprotein. An alternative strategy to ABL kinase
inhibition involves the development of small molecules
targeting BCR–ABL motifs that are remote from the
kinase domain (FIG. 3). Such compounds may potentially
be unaffected by mutations of the kinase domain that
make BCR–ABL1-positive leukaemic cells resistant to
imatinib.
GNF‑2. An alternative approach to the discovery of new
BCR–ABL inhibitors that differ to the traditional ATP-
competitive molecules is the use of high-throughput
differential cytotoxicity assays. Using such an approach,
Adrian et al. compared the antiproliferative activity of
approximately 50,000 compounds, representing 30 differ-
ent heterocyclic scaffolds, against non-transformed and
BCR–ABL1–transformed cells89. As a result, some novel
4,6-disubstituted pyrimidine compounds were found
to have similar inhibitory activity to imatinib. Among

nature reviews | drug discovery volume 6 | october 2007 | 841

© 2007 Nature Publishing Group
REVIEWS
O values of 752 nM and 3,269 nM, respectively. Notably,
NH2 HN CO2H
O ing BCR–ABL1 mutated at sites that directly contact
CH3 O O O imatinib (Thr315 and Phe317), or at positions Gly250
O S
N
ON012380
O O
N
H
N GNF‑2 is the leading compound of a new class of
GNF-2
Allosteric
site Substrate
site
BCR ABL
ATP
pocket
Imatinib (Gleevec)
N clinical trials of GNF‑2 in CML are eagerly awaited.
H H
N N N N
N O
N
Figure 3 | Different modes of BCR–ABL binding. Imatinib behaves as an ATP-competitive
130
inhibitor of the ABL tyrosine kinase with a Ki value of 85 nMNature Reviewsbinds
. Imatinib | DrugtoDiscovery
the ATP
site and an adjacent small hydrophobic pocket to effectively lock the kinase in an
inactive conformation that prevents the transfer of phosphate from ATP to target
substrates. By this mechanism imatinib induces cytogenetic responses in the majority of
patients with chronic myeloid leukaemia in the chronic phase with a remarkably
benign toxicity profile. The development of mutations within the ABL kinase domain
has prompted the development of other BCR–ABL inhibitors that have unique modes
of action. One such agent, ON012380, blocks the substrate binding site of ABL rather
than the ATP pocket, inhibiting this kinase with an IC50 value of 10 nM. Alternatively,
other regulatory sites on BCR–ABL are potential targets for small-molecule inhibitors.
ABL kinase has a myristoyl binding pocket at the C lobe. Myristoylation stabilizes ABL
in its inactive conformation. Although BCR–ABL is not myristoylated, it is expected
that compounds that bind to the myristoyl binding pocket can also lock the kinase in
its inactive configuration. GNF‑2 ((3 [6 [[4-(Trifluoromethoxy)phenyl]amino]
4-pyrimidinyl)benzamide) binds to this myristoyl pocket, resulting in potent ABL kinase
inhibition with exceptional enzymatic selectivity.
them, GNF‑2 — (3‑[6‑[[4-(trifluoromethoxy)phenyl]a
mino]‑4-pyrimidinyl]benzamide) — was identified as a
highly selective inhibitor of BCR–ABL1-dependent cell
proliferation that retains potency against most clinically
relevant imatinib-resistant BCR–ABL mutants. GNF‑2 is
the first compound shown to inhibit BCR–ABL kinase
by binding to the autoregulatory myristate binding cleft
of BCR–ABL located at the N‑terminus, spatially distant
from the active site of ABL kinase, which results in stabi-
lization of the protein in an inactive state89 (FIG. 3). This
mode of action probably contributes to the synergistic
effect between GNF‑2 and imatinib. GNF‑2 does not
compete with any ABL substrate, and inhibits the pro-
liferation of BCR–ABL1-expressing cells in a selective,
non-ATP-competitive manner with an IC50 of 138 nM,
but proved inactive against the catalytic domain of ABL
kinase. The selectivity of GNF‑2 was further supported
by its lack of activity against a panel of 63 kinases, includ-
ing FLT3, KIT, PDGFR, LCK and SRC. GNF‑2 inhibited
the growth of Ba/F3 cells expressing BCR–ABL1 E255V
or Y253H with IC50 values of 268 nM and 194 nM,
respectively. However, Ba/F3 cells carrying BCR–ABL1
M351T or H396P were less sensitive to GNF‑2, with IC50
842 | october 2007 | volume 6 www.nature.com/reviews/drugdisc
© 2007 Nature Publishing Group
GNF‑2 did not affect the viability of Ba/F3 cells express-
and Gln252 within the P-loop at concentrations up to
5–10 µM89.
putative allosteric ABL kinase inhibitors. Although the
mechanism of action of GNF‑2 is not yet fully character-
ized, its exceptional selectivity for BCR–ABL suggests that
this agent may be devoid of off-target effects and, there-
fore, of significant toxicity. Hence, GNF‑2 may represent
the first truly targeted antileukaemia drug. Results from
ON012380. ON012380 is a small-molecule TKI unre-
lated to ATP or other purine and pyrimidine nucleosides,
with approximately tenfold higher activity than imatinib
against BCR–ABL kinase90. In kinase inhibition assays,
ON012380 did not significantly affect the maximal velocity
of BCR–ABL despite the fact that the Km values were
significantly increased, suggesting that this compound
acts as a competitive inhibitor. Thus, it is believed that
ON012380 blocks the substrate binding site of BCR–ABL
rather than the ATP binding site. Unlike imatinib, it may
therefore be unaffected by mutations in the tyrosine
kinase domain90 (FIG. 3, TABLE 4). ON012380 competes
with natural substrates of BCR–ABL such as CRKL, but
not with ATP90. In doing so, ON012380 induced cell
death of BCR–ABL1-positive CML cells with a potency
greater than tenfold that of imatinib and caused regres-
sion of leukaemias induced by intravenous injection of
32DcI3 cells expressing BCR–ABL T315I kinase90. After
7 and 14 days, mice treated with ON012380 showed
significantly lower counts of leukaemic cells expressing
the T315I mutant than imatinib-treated or saline-treated
mice. Doses of 300 mg per kg of ON012380 produced
no signs of toxicity in mice. Interestingly, this agent also
inhibits the activity of the SFK LYN in the nanomolar
range (IC50 of 85 nM), and so is capable of overcoming
resistance conferred by LYN overexpression90. Although
ON012380 has shown remarkable in vitro activity, the
safety and activity of ON012380 has yet to be explored
in clinical trials.
ON01910. ON01910 is a small-molecule substrate-com-
petitive inhibitor of human polo-like kinase 1 (PLK1),
a member of the Polo family of protein kinases. PLK1
plays an important role in numerous aspects of cell-cycle
progression, including centrosome maturation, mitotic
spindle assembly and activation of the anaphase-pro-
moting complex91. Interestingly, ON01910 also inhibits
several tyrosine kinases, including wild-type BCR–ABL
(IC50 of 32 nM) and the SFKs SRC (IC50 of 155 nM) and
FYN (IC50 of 182 nM) 92. Phase I trials of ON01910 in
advanced metastatic cancers are in progress.
BCR–ABL T315I kinase inhibitors
The BCR–ABL1 T315I mutation, which can be detected
in 10–20% of patients with CML after failure of imatinib
therapy11,14, confers resistance to all currently approved
 REVIEWS

Table 4 | Selected compounds with activity against BCR–ABL T315I kinase

Compound Chemical structure Chemical Potency Potency Comments Refs
class against BCR– against BCR–
ABL WT ABL T315I
ON012380 Vinyl IC50 <10 nM IC50 <10 nM Potent inhibitor 86
HN CO2H
sulphone of LYN kinase
(IC50 of 85 nM);
O
O synergistic with
O O
S
imatinib

  O O

MK-0457 4,6 diamino IC50 of 10 nM IC50 of 30 nM Potent Aurora, FLT3 and 91–93
pyrimidine JAK2 kinase inhibitor;
N currently under
HN N evaluation in Phase I
H H
N studies in relapsed
N
AML, JAK2V617F-
N N S
O positive MPD and BCR-
ABL1 T315I-positive
N leukaemia
H3C

BIRB-796 Diaryl urea IC50 of 5.3 µM IC50 of 5.3 µM Undergoing clinical 104
O evaluation in patients
O N with inflammatory
N O diseases; in CML, IC50
N N N
H H not reached even at
20 µM for Ba/F3 cells
expressing BCR-ABL1
T315I

AP23846 O 2,6,9- IC50 of 500 nM IC50 of 297 nM Potent inhibitor of FLT3 72

P trisubstituted (IC50 of 10 nM) and SFKs
purine (IC50 of 0.1–13 nM);
derivatives however, it inhibits
HN
both parental and
N
N BCR-ABL1-positive
Ba/F3 cells
N N

AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; MPD, myeloproliferative disorder; SFKs, SRC family kinases.

agents for the treatment of CML, including nilotinib and
dasatinib24,25,31–33. Several avenues have been pursued in
an attempt to overcome T315I-mediated TKI resist-
ance, including the modelling of novel small-molecule
inhibitors amenable to the accommodation of structural
constraints imposed by this mutant, and the develop-
ment of agents that, like the above referenced ON12380,
target binding sites outside the ATP binding domain of
BCR–ABL. Alternatively, several TKIs designed to target
other kinases have shown off-target effects that include
the inhibition of BCR–ABL T315I kinase (TABLE 4).
Aurora kinase inhibitors. The human Aurora kinases
(AURKs) — AURKA (also known as STK6), AURKB
and AURKC — are essential for proliferation and correct
progression of cells through the mitotic phase of the cell
cycle93 (BOX 2). AURKA and AURKB are overexpressed
or gene amplified in several human malignancies.
MK‑0457 (formerly VX‑680) is an Aurora kinase inhibi-
tor (AKI) that has potent activity against tumour growth
in xenograft leukaemia models94 (TABLE 4). In enzyme-
activity assays, MK‑0457 inhibited wild-type ABL and
the ABL T315I mutant isoform, with IC50 values of
10 nM and 30 nM, respectively95. Furthermore, MK‑0457
inhibited the viability of Ba/F3 cells transformed by
wild-type, Y253F or T315I mutants of BCR–ABL96,97
(IC50 ~300 nM). A recent comparison of the AURKA–
MK‑0457 co-crystal structure at 2.9 Å resolution and that
of imatinib bound to ABL, revealed that these small mol-
ecules exploit non-overlapping sets of interactions with
their respective kinases98. MK‑0457 exploits a lipophilic
pocket that is only available in a closed conformation of
AURKA. As this pocket appears to be available in both
wild-type ABL and ABL T315I, MK‑0457 is therefore
able to bind to both enzymes and inhibit their activity,
with Kis of 30 nM and 42 nM, respectively98. Another
key difference when compared with imatinib, which
penetrates deeply into the ABL kinase domain, is that
MK‑0457 anchors itself firmly at the hinge region and
engages Asp381 at a much more superficial level within
the kinase domain99. This allows MK‑0457 to overcome
the potential steric constraints imposed by the mutant
ABL T315I kinase. MK‑0457 has shown activity against
BCR–ABL1 T315I-positive leukaemia in three patients

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REVIEWS
when given as a 5‑day continuous intravenous infu-
sion at doses from 12 mg per m2 per hour at 2–3‑week
intervals100. In a recent Phase I study in 11 patients with
BCR–ABL1 T315I-positive refractory CML, therapy
with MK‑0457 resulted in one major haematological
response, four minor haematological responses and
four cytogenetic responses (one CCyR, two partial and
one minimal)101. This activity was accompanied by the
inhibition of CRKL phosphorylation, a widely accepted
surrogate of ABL kinase activity. MK‑0457 steady-state
plasma concentrations were ≥1 µM at a dose level of ≥20
mg per m2 per hour, a concentration higher than that
predicted to inhibit ABL T315I kinase101. Ongoing stud-
ies will define the adequate dose schedule of MK‑0457
for patients with AML and CML. Combination trials of
MK‑0457 with dasatinib or nilotinib are planned.
VE‑465, an AKI chemically related to MK‑0457,
inhibited CRKL phosphorylation in Ba/F3 cells express-
ing wild-type BCR–ABL1 (IC50 of 2.0 µM) and BCR–
ABL1 T315I (IC50 of 3.5 µM), was additive with imatinib
against K562 cells, and prolonged survival of nude mice
injected with Ba/F3 cells expressing T315I102. AT9283,
KW2449 and PHA‑739358 (Ref. 103) are other AKIs
with activity against the T315I mutation currently under
evaluation in Phase I/II trials for patients with refractory
leukaemia, including BCR–ABL1 T315I-positive CML.
BIRB‑796. BIRB‑796 is a picomolar-level inhibitor
of p38 MAPK (also known as MAPK14)104,105, which
was discovered using combinatorial lead-optimization
strategies based on a simple biaryl urea compound104
(TABLE 4). Initial reports suggested that BIRB‑796 binds
selectively to ABL T315I (Kd of 41 nM)95,106 compared
with wild-type ABL (Kd of 1,500 nM) or any of the five
other imatinib-resistant ABL variants (Kd of 2,200 to
>10,000 nM)106. Although high concentrations of this
compound are necessary to inhibit autophosphorylation
of this mutant in Ba/F3 cells (IC50 of 1–2 µM), its selectiv-
ity against ABL T315I suggested a targeted application
of this agent for the treatment of patients bearing the
imatinib-insensitive T315I mutation95. However, when
tested in assays that directly measure inhibition rather
than binding, BIRB‑796 was found to be a moderately
effective inhibitor of Ba/F3 cells expressing BCR–ABL
T315I (IC50 of 2−3 µM)95,107, with negligible activity
(IC50 >10 µM) in parental and BCR–ABL1-positive Ba/F3
cells95,107. Notwithstanding the quantitative discrepancy
of the activity of BIRB‑796 in kinase-based and cell-based
assays, this TKI is proof-of-concept that it is possible to
inhibit BCR–ABL T315I with ATP-competitive com-
pounds, and supports medicinal chemistry efforts aimed
at developing more effective compounds against T315I.
XL228. XL228 is a multikinase inibitor with potent
activity against ABL, SFKs and insulin-like growth factor
type 1 receptor (IGF1R). In preclinical studies, XL228
has shown potent activity against the T315I mutation108.
A Phase I dose-finding study of intravenous XL228
is currently underway to evaluate the safety, pharma-
cokinetics and pharmacodynamics of this compound in
patients with CML or BCR–ABL1-positive B‑ALL.
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Other T315I inhibitors. The structural basis for the resist-
ance of BCR–ABL T315I to the 2,6,9-trisubstituted purine
derivative AP23464 lies in the inability of the phenol ring
attached to N9 of AP23464 to access the deep hydropho-
bic pocket of the ABL kinase active site76. To overcome
this physical constraint, a series of AP23464 analogues
have been developed with modifications at the N9 posi-
tion. Two such analogues, AP23848 and AP23980, were
marginally effective, with IC50 values of 6.4 µM and 5 µM,
respectively. However, AP23846, owing to the replace-
ment of the phenol moiety with the ethyl group of N9,
showed remarkable potency against BCR–ABL T315I76
and SFKs109 (TABLE 4). When the ethyl group at N9 was
substituted with hydrogen the resultant compound,
AP23980, lacked any inhibitory potency against BCR–
ABL T315I76. However, AP23846 inhibited the prolifera-
tion of Ba/F3 cells transformed by wild-type BCR–ABL1
and BCR–ABL1 T315I, but also the proliferation of the
parental Ba/F3 cells, thus indicating that off-target effects
may be, at least in part, responsible for the activity of this
compound76.
It has recently been shown that the benzotriazine
derivative TG100598 is a potent inhibitor of wild-type
ABL (IC50 of 0.4 nM) and BCR–ABL T315I (IC50 of
3.4 nM) kinases, as well as SRC kinase (IC50 of 3.6 nM)110.
TG101114 has demonstrated comparable potency to
that of TG100598 against T315I, but superior phar-
macokinetic properties with increased in vivo efficacy
against BCR–ABL T315I tumours, when given orally to
a xenograft SCID (severe combined immunodeficiency)
mouse model111. Interestingly, TG101114 has led to the
evolution of a new class of BCR–ABL inhibitors led by
TG101477, a compound that contains the dasatinib
thiazole core. TG101477 not only specifically inhib-
ited BCR–ABL1 T315I-positive cells that were isolated
from patients with CML with equal potency to that of
TG101114, but also showed increased selectivity com-
pared with dasatinib, inhibiting only 6 out of the 76 tested
kinases at 500 nM111.
Homoharringtonine, a pro-apoptotic cephalotaxine
ester derived from the evergreen tree Cephalotaxus har-
ringtonia k. koch var harringtonia, has recently been
shown to inhibit the proliferation of imatinib-resistant
cells expressing the T315I mutation, both in vitro and
in vivo112,113. These results provided the rationale for an
ongoing Phase II multicentre study designed to test the
efficacy of homoharringtonine in patients with CML
harbouring the T315I mutation after imatinib failure.
In summary, these data indicate that the structural
constraints posed by BCR–ABL T315I kinase can be
overcome by direct ATP-competitive inhibitors and by
agents with mechanisms of action other than ABL kinase
inhibition. However, the lack of specificity of some of
these drugs may result in untoward toxic effects that may
hinder their use in the clinic.
Lessons learned from BCR–ABL inhibition
The BCR–ABL oncoprotein has proved to be an ideal
target for validation of the clinical utility of TKIs in can-
cer10. Two major factors have been paramount in the
success of TKIs in CML: the identification of a critical
 REVIEWS

target, the BCR–ABL protein, which is sufficient to cause
CML5, and the development of an appropriate initial lead
compound, imatinib114.
Given our current ability to design specific TKIs, the
most important issue for the application of molecularly
targeted therapies to other cancers is the identifica-
tion of targets for drug development. In addition to
CML, other malignancies can also be ascribed to a
Box 2 | Inhibition of human Aurora kinases
The human Aurora kinases (AURKA, AURKB and AURKC) are key mitotic regulators that
are required for genomic stability93,128. Auroras are frequently overexpressed in cancer,
which is thought to be important for tumour formation and/or progression.
a | The domain structure, number of amino acids, and percentage of sequence homology
of human Auroras are depicted. Aurora kinases contain an NH2-terminal regulatory
domain (pale orange) and a catalytic kinase domain (grey). Phosphorylation at threonine
residues T287/T288 (AURKA), T232 (AURKB) or T195 (AURKC) within the activating
T‑loops is required for kinase activity. Two sequences, the destruction box (D-Box) and
the D‑Box-activating domain (DAD/A-Box), promote degradation at the end of mitosis.
These features have been confirmed in AURKA and AURKB. However, the structure of
AURKC is inferred by sequence alignment and appears to lack the A‑Box. AURKA
localizes to the duplicated centrosomes and to the spindle poles in mitosis. AURKA
overexpression compromises spindle-check-point function and inhibits cytokinesis.
AURKB relocates at the onset of anaphase from the chromosomal centrosome to the
microtubules that interdigitate at the spindle equator, regulating chromosome
condensation by phosphorylating histone H3 (Ref. 93). Aurora kinase inhibitors (AKIs) do
not inhibit cell-cycle progression. Rather, cells exposed to AKIs undergo mitosis with
normal kinetics and subsequently either re-replicate their genomes, resulting in
polyploidy, or undergo apoptosis in a pseudo G1 state. b | This depicts the structure of
ABL kinase domain bound to MK‑0457, which inhibits all Aurora kinase homologues and
the FLT3 kinase that is frequently mutated in acute myeloid leukaemia. Moreover,
MK‑0457 potently inhibits BCR–ABL T315I kinase, which renders chronic myeloid
leukaemia cells insensitive to imatinib, nilotinib and dasatinib. c | The Y‑shaped structure
of MK‑0457 avoids close encounter with leucine in Aurora kinases and isoleucine in
BCR–ABL T315 at the gatekeeper position. The four hydrogen bonds within the ABL
kinase are depicted (distances in Å).
a T287/T288 D-box
A-box
AURKA 403
132 383
A-box T232 D-box 57%
AURKB 344
76 327
T195 D-box 75%
AURKC 306
39 290
b MK-0457/ABL kinase c protein-kinase deregulation.
single molecular defect in a protein kinase, such as
ALK-positive anaplastic large-cell lymphoma115, mul-
tiple endocrine neoplasia with mutations in RET116
or gastrointestinal stromal tumours (GIST) carrying
gain-of-function mutations of KIT117. Although specific
TKIs will probably provide their maximal therapeutic
benefit when their target kinase is the main causative
abnormality, such agents may prove efficacious, either
alone or in combination, in genetically complex cancers
that have no obvious unique critical molecular drivers.
A prime example of the latter is the activity of the TKIs
gefitinib (Iressa; AstraZeneca) and erlotinib (Tarceva;
OSI Pharmaceuticals) in non-small cell lung cancer
(NSCLC) carrying mutant variants of EGFR118,119.
Several tools used in the development of BCR–ABL
inhibitors for CML will aid researchers in improving the
process of designing and optimizing efficacious TKIs for
other human cancers, including liquid chromatography–
mass spectrometry (LC–MS) for screening of libraries of
inhibitors that bind to different activation states of target
protein kinases; high-throughput medicinal chemistry
methods (for example, multicomponent reactions, solid-
phase parallel synthesis and diversity oriented synthe-
sis) coupled with structural biology of protein kinases
for the rapid detection, profiling and optimization of
lead compounds; exploration of signal-transduction
pathways through LC‑MS and other global phospho-
proteome strategies to identify ‘phospho-partners’ and
‘phospho-signatures’ linked to the target tyrosine kinase;
and murine cancer models to predict the in vivo activity
of targeted agents.
Last, the realization of the full potential of any given
TKI will require addressing the emergence of drug
resistance. Based on the CML experience showing
that a mutation of the conserved gatekeeper threonine
residue (T315I) prevents the binding of all clinically
approved ABL TKIs, structurally related mutations
have been described in other kinases such as KIT
(T670I) 120 in GIST; EGFR (T790M) 121 in NSCLC;
and FIP1L1-PDGFRα (T674I)122 in hypereosinophilic
syndrome that play central roles in the pathogenesis
60% of these conditions. Spurred by the discovery of TKIs
against BCR–ABL T315I in CML, several compounds
are being investigated as potential inhibitors of gate-
keeper mutants in NSCLC and GIST95. Undoubtedly,
the headway made by CML investigators will continue
to inspire the advance of molecularly targeted therapies
for a wide spectrum of human cancers associated with

Future directions
2.72 2.62 The pressing need for the development of novel agents
Thr315 capable of overcoming mechanisms of resistance to
gatekeeper
DFG 3.08 clinically approved TKIs, and a better understanding
motif of the structural biology of ABL kinase, has guided the
3.04 synthesis of an array of compounds with activity against
Pro396
Asp381 BCR–ABL1-positive leukaemic cells, and in some cases
with remarkably improved kinase specificity. The
rather limited approach of targeting the ABL kinase
domain directly has been recently challenged with the
design of two particularly promising agents, GNF‑2

nature reviews | drug discovery Nature Reviews | Drug Discovery volume 6 | october 2007 | 845
© 2007 Nature Publishing Group
REVIEWS

and ON012380, directed against ABL domains that are
distant from the ATP binding site. Because of their distinct
mode of BCR–ABL inhibition, these agents hold great
promise regarding the inhibition of ABL kinase domain
mutants and, owing to their enhanced kinase selectivity,
may be associated with benign toxicity profiles.
Furthermore, ON012380 inhibits the highly insensitive
mutant T315I, which mediates TKI resistance in a sig-
nificant proportion of patients with CML. Other agents,
such as the AKI MK‑0457, have also shown remarkable
activity against T315I. This encouraging preliminary
activity warrants investigation in larger series of patients
and a longer follow-up will be required to define the
durability of these responses.
To date, ABL kinase inhibition has not yielded cures
in patients with CML. The general consensus is that
combination approaches will be required to eradicate
BCR–ABL1-positive leukaemic clones. Although the
clinical relevance of the novel BCR–ABL kinase inhibi-
tors described here has yet to be proved, it is tempting to
speculate that the combination of potent dual ABL and
SFK inhibitors (for example, bosutinib) with TKIs that
target BCR–ABL motifs other than the kinase domain
(for example, GNF‑2), might provide a powerful strat-
egy to simultaneously inhibit multiple non-overlapping
BCR–ABL-related elements. The clinical development
of these combinations must be preceded by a systematic
effort to track their effects on molecular targets in vitro.
The speed with which BCR–ABL inhibitors have
been developed has exceeded expectations and fuels
optimism regarding the achievement of the final goal of
curing CML. To accomplish this goal it is essential that
the pace of scientific discoveries is matched with more
agile and flexible policies regarding drug approval by the
pertinent regulatory bodies. The swiftness with which
the FDA approved imatinib in 2001 has rapidly been
outpaced. Current regulations must be implemented to
enable highly promising BCR–ABL inhibitors to become
available sooner to patients with CML, even when other
active compounds may already be available.

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Acknowledgements
A.Q.-C. is perennially indebted to E. Schiele, J. Lado-Abeal and
L. Hayward for their ceaseless inspiration, and to D. L. Gibbons
for his unremitting remaking/remodelling/rethinking. W.H.:
“I understand the fury in your words, but not the words”.
Competing interests statement
The authors declare competing financial interests: see web
version for details.
DATABASES
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
ABL1 | ABL2 | BCL2 | BCR
OMIM:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
Analplastic large-cell lymphoma | chronic myeloid leukaemia |
GIST | lung cancer
UniProtKB: http://ca.expasy.org/sprot
AURKA | AURKB | AURKC | BLK | FGR | FYN | HCK| LCK | LYN |
SRC | YES
FURTHER INFORMATION
M. D. Anderson Leukemia Department:
http://www.mdanderson.org/departments/leukemia
All links are active in the online pdf