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IMATINIB – INHIBITS MULTIPLE KINASES

by Selleckchem | May 07 2012

INTRODUCTION:
SRC inhibitors are the molecules specific for targeting the non rector tyrosine kinase enzymes of SRC family and have the potential of inhibiting the 2 or more members of two SRC subfamilies, Fyn, Src. Fgr, Yes, Lck, Blk, Frk and Hck SRC kinases. These kinase enzymes take part in various pathways, so targeting them has became an attractive and valuable approach in the field of chemotherapy. Imatinib is commonly known as STI-571. Imatinib SRC inhibitor is a molecule originally named as STI571 and marketed by the company Novartis in the form of its mesylate salt hence known as STI-571 Imatinib Mesylate. This salt form is especially developed for targeting the cancer cells sparing the normal cells from them hence developed as personalized drug [1].
STI-571 structure reveals that this molecule is a derivative of 2-phenylaminopyrimidine. Its mechanism of action involves Imatinib binding at TK active site making them least active. It was studied that STI-571 IC50 is 3-4 micro Moles. One can purchase STI-571 by ordering it to STI-571 supplier for his laboratory and research uses. STI-571 price is almost around $40 for a vial of 500 mg while it can vary from Imatinib supplier to supplier. STI-571 solubility is easily achievable in water and DMSO as it gives a 200 mg/ml and 100 mg/ml solution in them respectively, while it is very poorly soluble in ethanol. STI-571 stability is more than two years if kept at -20 ºC or below.

IMATINIB IN CANCER:
STI-571 c-ABL inhibitor traps the BCR/ABL TK in nucleus of the chronic myelogenous leukemia cell lines hence stimulating the apoptosis in them [2]. It was reported that Imatinib stimulates the necrosis like cellular death in dependent of caspases in the leukemia cell lines [3]. This drug has also been tested for dermatological diseases [4]. Blocking of ABL kinases by Imatinib causes the disability of pathogenecity of Pox viruses [5] and also abrogates the diabetes-associated atherosclerosis [6]. This STI-571 VGFR inhibitor also offers a beam of hope in the complications of liver diseases like Portopulmonary hypertension (PoPH) condition [7]. It is also supposed that Imatinib shows some immunomodulatory effects as well as it has caused delay-type hypersensitivity in the primary T-cells in human and also inhibited the proliferation T-cells in vivo and in vitro respectively [8]. Immunostimulatory activities of Imatinib have also been seen in the gastrointestinal stromal tumors (GISTs) [9].

IMATINIB: CLINICAL AND PRECLINICAL ACHIEVEMENTS
Imatinib in combination with hydroxyurea, interferon alpha or Daunorubicin was observed to show synergistic effects on its efficiency against chronic myelogenous leukemia cell lines [10]. In cells of chronic myelogenous leukemia that are having chimerical BCR-ABL protein possessing constitutive TK activity, the medicine Imatinib acted like a specified targeted therapy [11]. The efficacy of this drug was observed in pediatric patients of CML assessed in a clinical trial phase IV [12]. STI-571 has also generated very favorable hematological and cytogenetic responses in patients of CML under clinical trial phase II [13]. In patients having cancer of head and neck region and metastatic non-small cell lung cancer, a combination of Imatinib along with Docetaxel has shown good synergistic effects [14]. A clinical study of phase II has proved the efficiency of Imatinib against the systemic mastocytosis patients [15]. STI-571 clinical trial of this medicine against GISTs has marked a new horizon of its therapy [16] and later on in a short time span, after that a clinical study under phase II has revealed its efficiency and safety profile in GISTs related patients [17]. Another phase II trial has reported the use of Imatinib against unresectable GISTs very successfully [18]. Imatinib has also entered the clinical analysis of patients related to systemic sclerosis (SSc)-associated active interstitial lung disease (ILD) [19] and also provided promising results in patients having diffused cutaneous systemic sclerosis (dcSSc) under a clinical study phase 2 [20]. Imatinib or STI-571 has also shown very good clinical results in patients of refractory Philadelphia chromosome–positive (Ph+) acute lymphoid leukemia (ALL) under phase II clinical trials [21].

REFERENCES:
1. Gambacorti, P.C., Part I: Milestones in personalised medicine--imatinib. Lancet Oncol., 2008.
2. Vigneri, P.a.W., J.Y., Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med., 2001.
3. Okada, M.e.a., A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity. Blood, 2003.
4. Scheinfeld, N., A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases. J Drugs Dermatol., 2006.
5. Reeves, P.M.e.a., Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med., 2005.
6. Lassila, M.e.a., Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol., 2004.
7. Tapper, E.B.e.a., Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc, 2009.
8. Dietz, A.B.e.a., Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood., 2004.
9. Zitvogel, L.K., G., Anticancer effects of imatinib via immunostimulation. Nature Medicine, 2011.
10. Thiesing, J.T.e.a., Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells. Blood, 2000.
11. Deininger, M.W.a.D., B.J., Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev., 2003.
12. Millot, F.e.a., Imatinib Is Effective in Children With Previously Untreated Chronic Myelogenous Leukemia in Early Chronic Phase: Results of the French National Phase IV Trial Journal of Clinical Oncology, 2010.
13. Sawyers, C.L.e.a., Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood, 2002.
14. Tsao, A.e.a., Phase II Trials of Imatinib Mesylate and Docetaxel in Patients with Metastatic Non-small Cell Lung Cancer and Head and Neck Squamous Cell Carcinoma. Journal of Thoracic Oncology, 2011.
15. Droogendijk, H.J.e.a., Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer., 2006.
16. DEMATTEO, R.P.e.a., Clinical Management of Gastrointestinal Stromal Tumors: Before and After STI-571. Human Pathology, 2002.
17. Oosterom, A.T.e.a., Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. The Lancet, 2001.
18. Blanke, C.D.e.a., Long-Term Results From a Randomized Phase II Trial of Standard- Versus Higher-Dose Imatinib Mesylate for Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing KIT. Journal of Clinical Oncology, 2008.
19. Khanna, D.e.a., Open-label pilot trial of imatinib mesylate (Gleevec) in the treatment of systemic sclerosis- associated active interstitial lung disease (SSc-ILD). Arthritis & Rheumatism, 2011.
20. Spiera, R.F.e.a., Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis, 2011.
21. Ottmann, O.G.e.a., A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood, 2001.