Farooq et al., IJPSR, 2013; Vol. 4(4): 1259-1268.

ISSN: 0975-8232

IJPSR (2013), Vol. 4, Issue 4

(Review Article)

Received on 20 December, 2012; received in revised form, 23 January, 2013; accepted, 13 March, 2013

TARGETING ONCOGENIC KINASE SIGNALING WITH SMALL MOLECULE KINASE

INHIBITOR IMATINIB
Saad Farooq*, M.H. Qazi and Maria Fareed Siddiqui
Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, 1 km Defense Road Lahore,
Pakistan
Keywords:
Kinases, Signaling, Cancer, Imatinib,
Pharmacology
Correspondence to Author:
Saad farooq
Centre for Research in Molecular
Medicine (CRiMM), The University of
Lahore, 1 km Defense Road Lahore,
Pakistan
E-mail: [email protected]

ABSTRACT: Protein tyrosine kinases (PTKs) are key players in

cellular signal transduction events and have essential roles in cell
growth, survival, differentiation and migration. Perturbations in protein
tyrosine kinase activity have been implicated in a number of
abnormalities, particularly cancer. Selective small molecule inhibitors
are potential therapeutic agents targeting protein kinases involved in
cancer and other diseases. The most dramatic clinical responses have
been observed in cancer types that are strictly dependent on oncogenic
kinases. In this case, targeting these kinases seems to be sufficient to
provoke apoptotic response, thus limiting the process of tumorigenesis.
Among tyrosine kinase inhibitors, imatinib mesylate (Gleevec;
Novartis) has demonstrated magnificent clinical efficacy in more than
one type of cancer and received FDA approval for treatment of chronic
myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST).
Imatinib has set a paradigm for the treatment and management of CML
as BCR-ABL kinase inhibitor. It binds kinase domain of PTK as an
ATP-competitive inhibitor thus preventing the interaction with effector
proteins and subsequent signaling pathway. Imatinib has excellent
pharmacokinetic profile and therapy is generally well tolerated with mild
to moderate toxicity which is manageable on reduction or
discontinuation of dosage. Despite its tremendous clinical outcome,
patients with advanced disease harbor resistance which is perhaps
multifactorial. Currently there is requisite of making strategies to
overcome resistance mechanisms and adverse effects in order to provide
maximum benefit to the patients.

INTRODUCTION: The human genome encodes

more than 500 protein kinases virtually contributing
in every signal transduction pathway through a
phosphotransfer cascade.
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90 genes have been identified in human genome

encoding tyrosine kinases, out of which 58 genes
encode receptor tyrosine kinases and 32 are nonreceptor tyrosine kinase encoding genes 1.
Receptor tyrosine kinases (RTKs) are cell surface
receptors spanning through membrane and they
contain N-terminal extracellular ligand binding
domain and intracellular C-terminal domain with
tyrosine kinase activity 2.

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Farooq et al., IJPSR, 2013; Vol. 4(4): 1259-1268.

Members of receptor tyrosine kinase family have

been implicated in critical cellular processes such as
cell survival and metabolism, proliferation and

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differentiation, migration and cell cycle control (Fig.

1) 3, 4.

FIG. 1: RECEPTOR TYROSINE KINASE SIGNALLING NETWORK. Upon activation of RTKs, adaptor molecule GRB2
binds to receptor, followed by the recruitment of SOS which exchange GDP for GTP on Ras, enabling its attachment to Raf kinase.
Activated Raf phosphorylates and activates MEK which in turn causes phosphorylation and activation of ERK. Furthermore, PLC
interacts with activated RTK and causes hydrolysis of PIP 2 into two second messengers IP 3 and DAG, both carry out variety of
responses. PI3K, AKT and STAT are also activated by RTKs and are involved in responses that are hallmarks of tumor cells.

There is involvement of nearly half of the protein

tyrosine kinase (PTK) receptors in various human
malignancies 3. There are different mechanisms of
abnormal PTK activity. Under such conditions, the
receptors are constitutively activated by either
amplification or mutational events. Constitutive
dimerization of RTKs takes place due to mutations
perturbing disulfide bonding in extracellular regions
of receptor, thus forming covalent dimer. Mutations
in transmembrane or juxtamembrane domains of
receptor may also facilitate dimerization. In other
mechanisms of aberrant tyrosine kinase activity,
fusion proteins are formed between kinase domains

of receptor and other proteins that occur normally as

dimers or oligomers. This results in constitutively
active kinase that promotes cell growth 5.
Development of Tyrosine Kinase Inhibitor:
Interest in the development of tyrosine kinase
inhibitors has been considerably enhanced for the
treatment of malignant and non-malignant
proliferative disorders 6. This suggests the potential
role of many of these kinases as therapeutic targets
for design of anti-cancer drugs that can inhibit their
tyrosine kinase activity. In past few years, there has
been substantial attention in the development of

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small inhibitors of protein kinases which are cellpermeable, diffusing across plasma membranes so
that they can reach intracellular target sites. Small
molecule kinase inhibitors are the class of drugs that
can specifically bind and inhibit the activity of
protein kinases. Most of the kinase inhibitors are
developed for the purpose of the maximum
selectivity towards a specific kinase of interest.
Majority of these inhibitors target the ATP-binding
site, but there is also a large number of non-ATP
competitive kinase inhibitors that target unique
allosteric sites 7.
The most exciting clinical response to the inhibitors
of protein kinases has been noticed for cancer types
that depict strict dependency of cell survival on the
targeted kinase 8. In such cases, complete blockage
of kinase activity seems to be sufficient for the
commencement of an apoptotic response in cancer
cells, which can cause disease stabilization in

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patients under treatment 9. The initial validation for

this concept appeared with the success of imatinib as
an inhibitor of BCR-ABL kinase in Chronic
Myelogenous Leukemia (CML) 10.
CML
is
characterized
cytogenetically
by
Philadelphia chromosome which is formed when
ABL (Abelson) proto-oncogene is translocated from
chromosome 9 and its 3 sequences combines with 5
sequences of BCR (breakpoint cluster region) gene
on chromosome 22. The BCR-ABL fusion gene and
its protein product with enhanced tyrosine kinase
activity was found to be present in majority of CML
patients and this 210-kD oncoprotein contains 902 or
927 amino acids of BCR fused with exons 211 of cAbl 11, 12, 13.
This protein product of fusion BCR-ABL is found in
more than 95% of CML patients and represents a
major contributing factor of the disease (Fig. 2) 14.

FIG. 2: TUMORIGENIC SIGNALING BY BCR-ABL KINASE. BCR-ABL kinase enables the cancer cells to evade apoptosis
through Ras-MAPK pathway and PI3K-AKT survival pathway.

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Additional studies indicated the significant protein

tyrosine kinase (PTK) activity in the transformation
function of BCR-ABL 15. After identification of
appropriate target the 2-phenylaminopyrimidines, the
first reported potent PTK inhibitors with selectivity
against the Abl and PDGF-R tyrosine kinases 16, 17,
were optimized for inhibition of the Abl and PDGFR by synthesizing a series of chemically related
compounds and the relationship between their
structure and activity was analyzed.
The most striking feature of these compounds was
inhibition of both v-Abl and the PDGF-R kinases.
Among them, Imatinib (formerly known as STI571
or CGP 57148B) emerged as the lead compound for
preclinical trials 18.The in vitro screening employed a
set of assays of isolated protein kinase enzymes for
initial chemical optimization. Although this sounds
straightforward now, this was too difficult in the late
1980s, when techniques for the recombinant

expression of active tyrosine protein kinase enzymes

were in their infancy 19, 20.
After the development of imatinib by rational drug
design, it was tested several times in preclinical
models. It was found that submicromolar
concentrations of this compound inhibited v-Abl,
PDGF
receptor,
and
KIT
receptor
autophosphorylation and signalling pathways in
which these kinases were involved 16, 17. The
targeting of KIT and PDGFR, other than BCR-ABL,
has broadened the clinical applications of imatinib in
diseases that involved deregulated PDGFR or KIT
kinases. Imatinib have had high profile achievement
exhibiting up to 80% response rates in chronic phaseCML patients 21.
Moreover, clinical efficacy of BCR-ABL tyrosine
kinase inhibitor imatinib in Chronic Myeloid
Leukemia provides a proof that BCR-ABL
oncoprotein is the primary cause of CML 10, 22.

TABLE 1: APPROVED KINASE INHIBITORS. There are hundreds of chemical compounds with unique structure that
selectively inhibit the variety of kinases. Some of the kinase inhibitors which are approved for their use in humans as anti-cancer
agents are listed in table 7
Name

Known Targets

Indication

Imatinib (Gleevec; Novartis)

Bcr-Abl, c-Abl, PDGFR, c-KIT,

CML, GIST

Nilotinib (Tasigna; Novartis)

Bcr-Abl, c-Abl, PDGFR, c-KIT, DDR1

Imatinib- refractory CML

Sorafenib (Nexavar; Bayer/Onyx)

Sunitinib (Sutent; Pfizer)

c-KIT, PDGFR, VEGFR

c-KIT, PDGR, VEGFR

Renal cancer
Renal cancer, imatinib-resistant GIST

Dasatinib (Sprycel; BristolMyers Squibb)

Bcr-Abl, SRC family, TEC family

Imatinib-resistant CML

Clinical Studies: Series of experiments showed the

potency and selectivity of imatinib towards Abl
tyrosine kinase, including BCR-ABL tyrosine kinase
23
. Imatinib specifically inhibited the proliferation of
myeloid cell lines that contained BCR-ABL as
colony forming assays taken from CML patients
when incubated with 1M imatinib showed
remarkable reduction (92-98%) in BCR-ABL
colonies while normal colony formation was not
affected 24, 25.
A phase I clinical trial with imatinib started in June
1998 10. Patients eligible for study were in the
chronic phase of CML and had failed therapy with
interferon-. After 300 mg or greater doses of orally
administered imatinib, 53 out of 54 patients achieved
a complete hematologic response. Clinical responses
were experienced within first three weeks of imatinib
therapy and maintained in 96% of patients with

median duration of 310 days follow up. At this dose

level of 300 mg or greater, major cytogenic
responses were appeared in 53% of patients and 13%
patients achieved a complete cytogenic response.
Phase I study was expanded after the success of
imatinib in chronic phase patients who had failed
with IFN- therapy and CML patients with myeloid
and lymphoid blast crisis and those with relapsed or
refractory Philadelphia chromosome positive acute
lymphoblastic leukemia (ALL) were included 22.
Patients were treated daily with doses ranging from
300-1000 mg of imatinib. Of these patients, 55%
with myeloid blast crisis responded to the therapy.
21% of these patients had cleared bone marrow
blasts to <5%. These and other clinical evidences
indicated the remarkable single agent activity of
imatinib in CML blast crisis and Ph positive ALL but
response were not inclined to be long-lasting.

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Success of phase I studies promoted the initiation of

the phase II studies of imatinib in late 1999. Imatinib
was administered as a single agent in the interferonresistant patients, in all phases of CML. In these
studies, imatinib was tested in more than 1000
patients over a time period of 6 to 9 months. The
results obtained from phase II studies were sufficient
to confirm the results seen in phase I studies and led
to the FDA approval of imatinib 26.
Physiochemical Properties: Imatinib is a synthetic
2phenylaminopyrimidine derivative and structural
formula of imatinib free base is shown in fig. 3 27.

FIG. 3: IMATINIB CONSISTS OF A PYRIDINE RING

(COLORED GREEN), AN AMINOPYRIMIDINE RING
(IN BLUE), A METHYLBENZENE RING (RED), A
BENZAMIDE RING (MAGENTA), AND AN NMETHYLPIPERAZINE RING (ORANGE).

Imatinib is marketed by its brand name Gleevec in

USA and by Glivec in Europe by Novartis
Pharmaceuticals as its mesylate salt. Gleevec filmcoated tablet contains imatinib mesylate (active
ingredient) equivalent to 400 mg of imatinib free
base. Imatinib mesylate is chemically designated as
4-((4-Methyl-1-piperazinyl)methyl)-N-(4-methyl-3((4-(3-pyridinyl)-2-pyrimidinyl)amino)-phenyl)
benzamide methanesulfonate 28.
Molecular weight of Imatinib mesylate is 589.7084
and molecular formula is C29H31N7O CH4SO3. It is
quadrivalent base with pKa (acid dissociation
constant) values ranging from 1.528.07, thus easily
soluble in water at pH 5.5 or less and solubility
decreases in aqueous buffer as the pH increases. The
drug substance is sparingly soluble at physiological
pH (50g/mL at pH 7.4) and is nearly insoluble in
neutral/alkaline aqueous buffers (pH 8.0). In polar
organic solvents, such as methyl alcohol (methanol)
and ethyl alcohol (ethanol), imatinib readily
dissolves. But in organic solvents of low polarity, it
is nearly insoluble and completely insoluble in noctanol, acetone and acetonitrile.

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Imatinib mesylate is physically white to off-white to

brownish/yellowish tinged crystalline powder.
Hydrolysis of amide bond does not takes place in
artificial gastric fluid at temperature of 37C and pH
1.2 for one hour, indicating the stability of imatinib
under these conditions 29.
Pharmacology of Imatinib: Imatinib is a small
molecule kinase inhibitor that blocks the tyrosine
kinase activity of the proteins involved in the
pathogenesis of Chronic Myelogenous Leukemia
(CML) and gastrointestinal stromal tumor (GIST) by
competing the ATP binding site on enzyme domain.
Hence, imatinib inhibits the BCR-ABL kinase, the
constitutive abnormal tyrosine kinase fusion protein
created by reciprocal translocation between the
chromosome 9 and chromosome 22, called
Philadelphia translocation. 95% of the patients
affected by CML are reported Philadelphia
chromosome positive.
Similarly, imatinib is a potent inhibitor of the Kit
receptor tyrosine kinase and displays activity towards
GIST by suppressing the tyrosine kinase activity of
mutated c-kit receptor broadly expressed (85%) in
GIST, a subgroup of soft-tissue sarcomas 30. Many
studies demonstrate that imatinib is not entirely
specific; it is also active against the mutated receptor
tyrosine kinase for platelet-derived growth factor
(PDGF) 31 and encourages the activation of natural
killer (NK) cells 32.
Imatinib is given orally and is prepared in hard
capsules or tablets (United States) as its salt (imatinib
mesylate or methane sulfonic acid). Each tablet of
Gleevec contains 100 or 400 mg of imatinib free
base. The recommended dosage for adult Chronic
Myelogenous Leukemia patients in its various stages
(chronic, accelerated or blast crisis) and for Kitpositive GIST that become metastatic and/or
unresectable, once daily dose of 400 mg or 600 mg is
given with a meal.
In children with CML, range of daily doses is from
260 mg/m2 to 340 mg/m2. The treatment is continued
until progression of disease or intolerable toxicity 30.
Dosage of Gleevec increases from 400 mg to 600 mg
for patients suffering from chronic phase disease. For
patients in accelerated phase or blast crisis, dosage
increases from 600 mg to 800 mg, given as 400 mg
twice a day 28.

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In vitro studies indicate that the contents of the

capsule can be dissolved and are stable in water and
apple juice but not in milk, orange juice or cola 33.
Imatinib should be stored at 25 C (77F); excursions
are tolerable from 15 to 30C (59-86F) and dispense
it in a tight container 28.
Pharmacodynamics of Imatinib:
Mechanism of Action: Imatinib functions as an
ATP-competitive inhibitor with a Ki value of 85 nM

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16

. Imatinib binds to ATP site of kinases and an

adjacent small hydrophobic pocket, hence blocking
the kinase activity and preventing the transfer of
phosphate group from ATP to target substrates. The
crystal structure of Abl kinase domain in complex
with imatinib reveals that it binds to inactive
conformation of Abl (Fig. 4) 34. In this way, imatinib
induces cytogenetic responses in patients with CML
in chronic phase.

FIG. 4: BINDING OF TYROSINE KINASE INHIBITOR IMATINIB TO ABL KINASE: a) The ribbon representation of Abl
kinase domain bound to imatinib. b) This schematic diagram depicts interactions made by imatinib with Abl. Dotted lines indicate
hydrogen bonds along with their distances. Residues making van der Waals interactions with imatinib are circled with dotted lines.

Drug Interactions: Imatinib is mainly metabolized

by CYP3A4 and CYP3A5 isozymes. So when
imatinib is co-administered with drugs that inhibit
the activity of CYP3A4 and CYP3A5, its metabolism
can be reduced and plasma concentrations increased.
Major activator of CYP3A4 and CYP3A5 isozyme
system may increase metabolism and reduce
exposure to imatinib (e.g. carbamazepine,
barbiturates, dexamethasone, rifampicin, phenytoin,
and St Johns Wort (hypericum)) 29. Drug-drug
interaction analyses of imatinib have focused on the
potential alteration in activity of CYP3A4 and
CYP3A5. In general, precautionary measures should
be taken for drug interactions while administering

imatinib with substrates or modulators of the CYP3A

family.
Adverse effects of Imatinib and their Clinical
Management: In clinical studies, there is good
tolerance of imatinib. Along with many benefits of
imatinib treatment, adverse effects are also
accompanied that must be managed in order to the
adherence of patients to treatment. Adverse effects
for imatinib are reported mild to moderate (grade 1
or 2) and appears to be easily manageable and
reversible without reduction in dosage or permanent
discontinuation of therapy. Most commonly
occurring adverse reactions that patients may
experience are gastrointestinal reactions (nausea,

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vomiting, and diarrhea), lethargic conditions edema,

muscle cramps, and different types of rashes are
developed 35, 36.
Resistance to Imatinib: In spite of significant
clinical efficacy of imatinib in treating CML,
resistance to therapy occurs in patients with
advanced disease. Clinical studies indicated that
patients in chronic phase show long lasting responses
whereas most patients responding in blast crisis
relapse despite persistent therapy 10, 22, 37.
Mechanisms of resistance to imatinib therapy
identified from in vitro studies include several-fold
increase in quantity of BCR-ABL oncoprotein, BRCABL gene amplification, and multidrug resistance Pglycoprotein overexpression 38, 39, 40.
The most frequent mechanism of resistance found in
these studies was overexpression of BCR-ABL
mRNA and its protein product. In patients who
acquired resistance to imatinib showed mutations in
Abl tyrosine kinase domain 41 sequencing of ATPbinding site and activation loop of Abl kinase
domain indicated point mutation of cytosine to
thymidine, resulting in replacement of single amino
acid residue at position 315 designated as T315I.
Threonine 315 is essential for the formation of
hydrogen bond with imatinib. The substituted
isoleucine lacks oxygen atom thus preventing the
bond formation and this isoleucine was also
predicted to produce steric clash with imatinib, so
this residue was termed gatekeeper for imatinib.
Imatinib in Combinations:
Combination with Taxane therapy: As imatinib
inhibits tyrosine kinase signaling by PDGFR,
imatinib was used with injected paclitaxel in a study
and the inhibition of PDGFR signaling pathway in a
mouse model was examined to produce substantial
therapeutic effects against prostate cancer bone
metastases 42. Impact of paclitaxel and imatinib on
mice under experiment was observed as
monotherapy as well as in conjunction. In mice
treated with paclitaxel, tumor prevalence was 17 of
20 and in mice treated with imatinib, incidence of
tumor was found to be 10 of 20 with median weight
of 1.8g.

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Tumor incidence was 7 out of 20 in mice which were

treated with the combination of imatinib and
paclitaxel and the median weight of tumor was 0.6g.
The smaller tumor size among mice treated with
imatinib reflects decreased cell divisions of tumor
cells and increased apoptosis or both.
Analysis of PDGFR status in bone marrow biopsies
of androgen-independent prostate cancer (AIPC)
revealed no readily discernible alteration in PDGFR
expression after 30 days of imatinib therapy alone 43.
However, in combination therapy of imatinib plus
docetaxel, there was noticeable decline in tumor
expressing PDGFR.
Secondary type glioblastomas are associated with
over activity of PDGFR forming autocrine loop,
which participate in tumor progression and leads to
transformation process, manifesting more malignant
phenotype 44, 45.
Clinical trials using only imatinib therapy for
recurrent glioblastomas resulted in increased
progression free survival for only a few patients after
six months 46, 47. Docetaxel is used in different types
of cancers and its therapy for treatment of
glioblastomas has shown negligible or no significant
response 48, 49.
The combine effect of docetaxel and imatinib was
observed in primary glioma cell lines 50. Docetaxel
alone induced apoptosis in 4.3-10% cells, whereas
imatinib alone caused apoptosis in 4.7-7% cells, but
docetaxel and imatinib when introduced together
induced apoptosis in 13.8-40.1% cells. Imatinib and
taxol induce apoptosis via different signaling
pathways (Fig. 5).
An experiment was set in which human breast cancer
cell lines were incubated with ascending
concentrations of doxorubicin and imatinib used
alone or in combination 51.
Both drugs revealed their additive therapeutic effects
on cell growth inhibition which was enhanced as
compared to their individual effect. Combination of
Imatinib with radiation on breast cancer cells was
also evaluated and the surviving fraction of
cancerous cells was reduced 51.

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.
FIG. 5. ILLUSTRATION OF ADDITIVE EFFECTS OF IMATINIB AND TAXOL. In vitro, paclitaxel (taxol) polymerizes
tubulin and stabilize the microtubules. This causes the cell cycle arrest in the G2/M phase and ultimately apoptosis. Taxol initiates
death signals that causes upregulation of BAX and ER stress, increasing intracellular Ca++ that upregulates calpain. Taxol also
triggers extrinsic caspase pathway by upregulating TNF- and TRAIL. Bcl-xL phosphorylation promotes cytochrome c release from
mitochondria which associates with apaf-1 and procaspase-9, thus activating intrinsic apoptotic pathway. Calpain cleaves and
activates procaspase-3 which in turn cleaves fodrin, PARP and DFF45 leading to apoptosis.

CONCLUSION AND PERSPECTIVES: Imatinib

mesylate revolutionized the treatment and outcome
of chronic myeloid leukemia and certain other cancer
types. It is very effective against some types of
leukemia that express BCR-ABL1 gene product
whose tyrosine kinase domain is best known target of
imatinib. This drug has many possible targets and
can be given in some combinations which expand its
usage in several abnormalities. Other possible
combination therapies can be made optimum by
considering the signalling pathways affected by

imatinib and other drugs. Although clinical efficacy

of this drug is significant in Philadelphia
chromosome positive CML patients, some patients
become resistant to the therapy due to several
reasons mainly mutations in Abl kinase domain. In
order to overcome its drawbacks, amendments can be
made in its chemical structure where certain
functional groups can be added or substituted.
Another option is the development of similar and
improved small molecules with inhibitory activity
against tyrosine kinases.

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A new wave of tyrosine kinase inhibitors is currently

under clinical practices and enabled the imatinibresistant CML patients to respond to the therapy.
With the development of new kinase inhibitors, there
could be chance of discovery of new possible kinase
targets which may broaden the application of
tyrosine kinase inhibitors (TKIs).
ACKNOWLEDGMENT: I would like to
acknowledge Ms. Maria Fareed Siddiqui for her
valuable idea of writing the paper on this topic and
her critical contribution to the work. Additionally, I
am grateful to Prof. Dr. M.H. Qazi for his kindness
and interest in writing of this review paper.
REFERENCES
1.

2.
3.
4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Robinson DR, Wu YM, and Lin SF: The protein tyrosine

kinase family of the human genome. Oncogene, 2000; 19:
55485557.
Schlessinger J: Cell signaling by receptor tyrosine kinases.
Cell, 2000; 103: 211225.
Blume-Jensen P and Hunter T: Oncogenic kinase signalling.
Nature, 2001; 411: 355365.
Ullrich A and Schlessinger J: Signal transduction by
receptors with tyrosine kinase activity. Cell, 1990; 61: 203
212.
Heldin CH: Protein Tyrosine Kinase Receptor Signaling
Overview, in Handbook of Cell Signaling (Bradshaw RA,
and Dennis EA eds) 2003; 391-396, Elsevier Science (USA).
Cohen P: Protein kinases--the major drug targets of the
twenty-first century? Nat Rev Drug Discov, 2002; 1: 309
315.
Zhang J, Yang PL, and Gray NS: Targeting cancer with
small molecule kinase inhibitors. Nat Rev Cancer, 2009; 9:
2839.
Sharma SV, and Settleman J: Oncogene addiction: setting
the stage for molecularly targeted cancer therapy. Genes
Dev, 2007; 21: 32143231.
Shah NP, Kasap C, Weier C, Balbas M, Nicoll JM,
Bleickardt E, Nicaise C, and Sawyers CL: Transient potent
BCR-ABL inhibition is sufficient to commit chronic myeloid
leukemia cells irreversibly to apoptosis. Cancer Cell, 2008;
14: 485493.
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E,
Ford JM, Lydon NB, Kantarjian H, Capdeville R, OhnoJones S, and Sawyers CL: Efficacy and safety of a specific
inhibitor of the BCR-ABL tyrosine kinase in chronic
myeloid leukemia. N Engl J Med, 2001; 344: 1031-7.
Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, Klein
A, Bartram CR, and Grosveld G: Localization of the c-abl
oncogene adjacent to a translocation break point in chronic
myelocytic leukemia. Nature, 1983; 306: 239-242.
Shtivelman E, Lifshitz B, Gale RP, and Canaani E: Fused
transcript of abl and bcr genes in chronic myelogenous
leukaemia. Nature, 1985; 315: 550-554.
Ben-Neriah Y, Daley GQ, Mes-Masson A-M, Witte ON, and
Baltimore D: The chronic myelogenous leukemia-specific
P210 protein is the product of the bcr/abl hybrid gene.
Science, 1986; 233: 212-214.
Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, and Jones RJ:
Inhibition of apoptosis by BCR-ABL in chronic myeloid
leukemia. Blood, 1994; 83: 20382044.

International Journal of Pharmaceutical Sciences and Research

ISSN: 0975-8232
15. Lugo TG, Pendergast AM, Muller AJ, and Witte ON:
Tyrosine kinase activity and transformation potency of bcrabl oncogene products. Science, 1990; 247: 1079-1082.
16. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M,
Regenass U, and Lydon NB: Selective inhibition of the
platelet-derived growth factor signal transduction pathway
by a protein-tyrosine kinase inhibitor of the 2-phenylamino
pyrimidine class. Proc Natl Acad Sci USA, 1995; 92: 2558
2562.
17. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M,
Druker BJ, and Lydon NB: Inhibition of the Abl proteintyrosine kinase in vitro and in vivo by a 2phenylaminopyrimidine derivative. Cancer Res, 1996; 56:
100-104.
18. Druker BJ and Lydon NB: Lessons learned from the
development of an abl tyrosine kinase inhibitor for chronic
myelogenous leukemia. J Clin Invest, 2000; 105: 37.
19. Foulkes JG, Chow M, Gorka C, Frackelton AJ, and
Baltimore D: Purification and characterization of a proteintyrosine kinase encoded by the Abelson murine leukemia
virus. J Biol Chem, 1985; 260: 80707.
20. Lydon NB, Adams B, Poschet JF, Gutzwiller A, and Matter
A: An E. coli expression system for the rapid purification
and characterization of a v-abl tyrosine protein kinase.
Oncogene Res, 1990; 5: 16173.
21. OBrien SG, Guilhot F, Larson RA, Gathmann I, Baccarani
M, Cervantes F, Cornelissen J.J., Fischer T, Hochhaus A,
Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J,
Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman
JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE,
Capdeville R, and Druker BJ: Imatinib compared with
interferon and low-dose cytarabine for newly diagnosed
chronic phase chronic myeloid leukemia. N Engl J Med,
2003; 348: 9941004.
22. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF,
Ford JM, Capdeville R, and Talpaz M: Activity of a specific
inhibitor of the BCR-ABL tyrosine kinase in the blast crisis
of chronic myeloid leukemia and acute lymphoblastic
leukemia with the Philadelphia chromosome. N Engl J Med,
2001; 344: 1038-1042.
23. ODwyer ME and Druker BJ: The role of the tyrosine kinase
inhibitor STI571 in the treatment of cancer. Curr Cancer
Drug Targets, 2001; 1: 4957.
24. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM,
Fanning S, Zimmermann J, and Lydon NB: Effects of a
Selective Inhibitor of the Abl Tyrosine Kinase on the Growth
of Bcr-Abl Positive Cells. Nat Med, 1996; 2: 561-566.
25. Deininger MW, Goldman JM, Lydon N, and Melo JV: The
Tyrosine Kinase Inhibitor CGP57148B Selectively Iinhibits
the Growth of BCR-ABL-Positive Cells. Blood, 1997; 90:
3691-3698.
26. Druker BJ: STI571 (Gleevec) as a paradigm for cancer
therapy. Trends Mol Med, 2002; 8(4Suppl.): S14-8.
27. Winger JA, Hantschel O, Superti-Furga G, and Kuriyan J:
The structure of the leukemia drug imatinib bound to human
quinone reductase 2 (NQO2). BMC Struct Biol, 2009; 9: 7.
28. Novartis Pharma; prescribing information (online). Available
from
URL:
http://www.Gleevec.com/info/page/prescribing_info
(Accessed 2005 Jun 16).
29. Peng B, Lloyd P, and Schran H: Clinical pharmacokinetics
of imatinib. Clin Pharmacokinet, 2005; 44: 87994.
30. Leveque D and Maloisel F: Clinical pharmacokinetics of
imatinib mesylate. In Vivo, 2005; 19: 77-84.
31. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S,
Drucker BJ, and Lydon NB : Abl protein-tyrosine kinase
inhibitor STI571 inhibits in vitro signal transduction

1267

Farooq et al., IJPSR, 2013; Vol. 4(4): 1259-1268.

32.

33.

34.

35.

36.

37.

38.

39.

40.

mediated by c-kit and platelet-derived growth factor

receptors. J Pharmacol Exp Ther, 2000; 295: 139-145.
Borg C, Terme M, Taieb J, Menard C, Flament C, Robert C,
Maruyama K, Wakasugi H, Angevin E, Thielemans K, Le
Cesne A, Chung-Scott V, Lazar V, Tchou I, Crepineau F,
Lemoine F, Bernard J, Fletcher JA, Turhan A, Blay JY,
Spatz A, Emile JF, Heinrich MC, Mecheri S, Tursz T, and
Zitvogel L: Novel mode of action of c-kit tyrosine kinase
inhibitors leading to NK cell-dependent antitumor effects. J
Clin Invest, 2004; 114: 379-388.
Champagne MA, Capdeville R, Krailo M, Qu W, Peng B,
Rosamilia M, Therrien M, Zoellner U, Blaney SM, and
Bernstein M: Imatinib mesylate (STI 571) for treatment of
children with Philadelphia chromosome-positive leukemia:
results from a Childrens Oncology Group phase 1 study.
Blood, 2004; 104: 2655-2660.
Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach
DR, Miller WT, Clarkson B, and Kuriyan J: Crystal
structures of the kinase domain of c-Abl in complex with the
small molecule inhibitors PD173955 and imatinib (STI-571).
Cancer Res, 2002; 62: 42364243.
Hensley ML and Ford JM: Imatinib treatment: specific
issues related to safety, fertility, and pregnancy. Semin
Hematol, 2003; 40(suppl 2): 2125.
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele
AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA,
Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman
SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker
BJ, Corless C, Fletcher CD, and Joensuu H: Efficacy and
safety of imatinib mesylate in advanced gastrointestinal
stromal tumors. N Engl J Med, 2002; 347: 472480.
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer
C, Gambacorti-Passerini C, Niederwieser D, Resta D,
Capdeville R, Zoellner U, Talpaz M, and Druker B:
Hematologic and Cytogenetic Responses to Imatinib
Mesylate in Chronic Myelogenous Leukemia. N Engl J Med,
2002; 346: 645652.
Tipping AJ, Mahon FX, Lagarde V, Goldman JM, and Melo
JV: Restoration of sensitivity to STI571 in STI571-resistant
chronic myeloid leukemia cells. Blood, 2001; 98: 3864
3867.
Mahon FX, Deininger MW, Schultheis B, Chabrol J,
Reiffers J, Goldman JM, and Melo JV: Selection and
characterization of BCR-ABL positive cell lines with
differential sensitivity to the tyrosine kinase inhibitor
STI571: diverse mechanisms of resistance. Blood, 2000; 96:
10701079.
Weisberg E and Griffin JD: Mechanism of resistance to the
ABL tyrosine kinase inhibitor STI571 in BCR/ABLtransformed hematopoietic cell lines. Blood, 2000; 95: 34983505.

ISSN: 0975-8232
41. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R,
Rao PN, and Sawyers CL : Clinical resistance to STI-571
cancer therapy caused by BCR-ABL gene mutation or
amplification. Science, 2001; 293: 876880.
42. Uehara H, Kim SJ, Karashima T, Shepherd DL, Fan D, Tsan
R, Killion JJ, Logothetis C, Mathew P, and Fidler IJ: Effects
of blocking platelet-derived growth factor-receptor signaling
in a mouse model of experimental prostate cancer bone
metastases. J Natl Cancer Inst, 2003; 95: 458-470.
43. Mathew P, Thall PF, Jones D, Perez C, Bucana C, Troncoso
P, Kim SJ, Fidler IJ, and Logothetis C: Platelet-derived
growth factor receptor inhibitor imatinib mesylate and
docetaxel: a modular phase I trial in androgen-independent
prostate cancer. J Clin Oncol, 2004; 22: 33239.
44. Hermanson M, Funa K, Hartman M, Claesson-Welsh L,
Heldin CH, Westermark B, and Nister M: Platelet-derived
growth factor and its receptors in human glioma tissue:
expression of messenger RNA and protein suggests the
presence of autocrine and paracrine loops. Cancer Res, 1992;
52: 3213-9.
45. Westermark B, Heldin CH, and Nister M: Platelet-derived
growth factor in human glioma. Glia, 1995; 15: 257-63.
46. Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert
B, Clement PM, Frenay M, Rampling R, Stupp R, Kros JM,
Heinrich MC, Gorlia T, Lacombe D, and van den Bent MJ:
Phase II study of imatinib in patients with recurrent gliomas
of various histologies: a European Organisation for Research
and Treatment of Cancer Brain Tumor Group Study. J Clin
Oncol, 2008; 26: 4659-65.
47. Katz D, Segal A, Alberton Y, Jurim O, Reissman P, Catane
R, and Cherny NI: Neoadjuvant imatinib for unresectable
gastrointestinal stromal tumor. Anticancer Drugs, 2004; 15:
599-602.
48. Sanson M, Napolitano M, Yaya R, Keime-Guibert F, Brot
P, Hoang-Xuan K, and Delattre JY: Second line
chemotherapy with docetaxel in patients with recurrent
malignant glioma: a phase II study. J Neurooncol, 2000; 50:
245-9.
49. Forsyth P, Cairncross G, Stewart D, Goodyear M, Wainman
N, and Eisenhauer E: Phase II trial of docetaxel in patients
with recurrent malignant glioma: a study of the National
Cancer Institute of Canada Clinical Trials Group. Invest New
Drugs, 1996; 14: 203-6.
50. Kinsella P, Clynes M, and Amberger-Murphy V: Imatinib
and docetaxel in combination can effectively inhibit glioma
invasion in an in vitro 3D invasion assay. J Neurooncol,
2011; 101: 189-98.
51. Weigel MT., Dahmke L, Schem C, Bauerschlag DO, Weber
K, Niehoff P, Bauer M, Strauss A, Jonat W, Maass N, and
Mundhenke C: In vitro effects of imatinib mesylate on
radiosensitivity and chemosensitivity of breast cancer cells.
BMC Cancer 2010; 10: 412.

How to cite this article:

Farooq S, Qazi MH and Siddiqui MF: Targeting oncogenic kinase signaling with small molecule kinase inhibitor Imatinib. Int J
Pharm Sci Res 2013; 4(4); 1259-1268.

International Journal of Pharmaceutical Sciences and Research

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