TARGETING ONCOGENIC KINASE SIGNALING WITH SMALL MOLECULE KINASE INHIBITOR IMATINIBHTML Full Text
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
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.
Kinases, Signaling, Cancer, Imatinib, Pharmacology
INTRODUCTION: The human genome encodes more than 500 protein kinases virtually contributing in every signal transduction pathway through a phosphotransfer cascade.
90 genes have been identified in human genome encoding tyrosine kinases, out of which 58 genes encode receptor tyrosine kinases and 32 are non-receptor 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.
Members of receptor tyrosine kinase family have been implicated in critical cellular processes such as cell survival and metabolism, proliferation and 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, PLCγ interacts with activated RTK and causes hydrolysis of PIP2 into two second messengers IP3 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 small inhibitors of protein kinases which are cell-permeable, 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 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 2–11 of c-Abl 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.
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 PDGF-R 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 phase-CML 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
|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)||c-KIT, PDGFR, VEGFR||Renal cancer|
|Sunitinib (Sutent; Pfizer)||c-KIT, PDGR, VEGFR||Renal cancer, imatinib-resistant GIST|
|Dasatinib (Sprycel; Bristol–Myers 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 1µM 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-α. 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-α 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.
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 interferon-resistant 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 2‐phenylaminopyrimidine 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 N-METHYLPIPERAZINE 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 film-coated 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 1.52–8.07, 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 (50µg/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 n-octanol, acetone and acetonitrile.
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 37°C 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 Kit-positive 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.
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 (77°F); excursions are tolerable from 15 to 30°C (59-86°F) 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 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 John’s 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, 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, BRC-ABL gene amplification, and multidrug resistance P-glycoprotein 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 ATP-binding 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.
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.
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-α 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 α–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.
A new wave of tyrosine kinase inhibitors is currently under clinical practices and enabled the imatinib-resistant 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.
- Robinson DR, Wu YM, and Lin SF: The protein tyrosine kinase family of the human genome. Oncogene, 2000;19: 5548–5557.
- Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell, 2000; 103: 211–225.
- Blume-Jensen P and Hunter T: Oncogenic kinase signalling. Nature, 2001; 411: 355–365.
- 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: 28–39.
- Sharma SV, and Settleman J: Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev, 2007;21: 3214–3231.
- 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: 485–493.
- Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones 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: 2038–2044.
- Lugo TG, Pendergast AM, Muller AJ, and Witte ON: Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science, 1990; 247: 1079-1082.
- 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.
- Buchdunger E,Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, and Lydon NB: Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res, 1996; 56: 100-104.
- 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: 3–7.
- Foulkes JG, Chow M, Gorka C, Frackelton AJ, and Baltimore D: Purification and characterization of a protein-tyrosine kinase encoded by the Abelson murine leukemia virus. J Biol Chem, 1985; 260: 8070–7.
- Lydon NB, Adams B, Poschet JF, Gutzwiller A, and Matter A: An E. coli expression system for the rapid purification and characterizationof a v-abl tyrosine protein kinase. Oncogene Res, 1990; 5: 161–73.
- O’Brien 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: 994–1004.
- 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.
- O’Dwyer ME and Druker BJ: The role of the tyrosine kinase inhibitor STI571 in the treatment of cancer. Curr Cancer Drug Targets, 2001; 1: 49–57.
- 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.
- 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.
- Druker BJ: STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol Med, 2002; 8(4Suppl.): S14-8.
- 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.
- Novartis Pharma; prescribing information (online). Available from URL: http://www.Gleevec.com/info/page/prescribing_info (Accessed 2005 Jun 16).
- Peng B, Lloyd P, and Schran H:Clinical pharmacokinetics of imatinib. Clin Pharmacokinet, 2005; 44: 879–94.
- Leveque D and Maloisel F: Clinical pharmacokinetics of imatinib mesylate. In Vivo, 2005; 19: 77-84.
- 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 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 inhibitorsleading 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 Children’s 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: 4236–4243.
- Hensley ML and Ford JM: Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol, 2003; 40(suppl 2): 21–25.
- 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: 472–480.
- 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: 645–652.
- 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: 1070–1079.
- Weisberg E and Griffin JD: Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood, 2000; 95: 3498-3505.
- 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: 876–880.
- 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.
- 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: 3323–9.
- 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.
- Westermark B, Heldin CH, and Nister M: Platelet-derived growth factor in human glioma. Glia, 1995; 15: 257-63.
- 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.
- 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.
- Sanson M,Napolitano M, Yaya R, Keime-Guibert F, Broët 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.
- 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.
- 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.
- 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.
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
20 December, 2012
23 January, 2013
13 March, 2013
01 April, 2013