MASITINIB – A DIVERSIFIED TYROSINE KINASE INHIBITOR

by Selleckchem | Apr 10 2012

TYROSINE KINASES AND MASITINIB
Different types of chemotherapeutic drugs are there that target different tyrosine kinase receptors due to their role in different types of cancers e.g., pancreatic and gastrointestinal tumors [1], different inflammatory conditions and other diseases. Major focus is being given to VEGF-R (Vascular endothelial growth factor receptor), PDGF-R (Platelet derived growth factors), FGF-R3 (Fibroblast growth factor receptor 3), c-Kit and FAKs (Focal adhesion kinases). These proto-oncogenes have different functions in the cells. PDGF-R function in the proliferation and survival of cell, FGF-R3 controls mitotic and differentiation processes. c-Kit, a cytokine receptor is expressed on mast cell surface and can be involved in germ cell tumors, GISTs (gastrointestinal stromal tumors) and leukemia etc. and FAKs contribute in metastasis. All of these TKs, therefore, provide an attractive target for anti cancer drugs.
Pan-TKI orally administered TKI, Masitinib got popular due to its successes in clinical and preclinical studies. Masitinib the c-Kit inhibitor also targets FAKs, PDGF-R, and FGF-R3 in cancer [2]. TKIs along with Masitinib effect adenocarcinomas in pancreatic cancer [3] and also target EGFR pathway [4] and hedgehog signaling in pancreatic cancer [5]. Successful inhibition of c-Kit by Masitinib c-Kit inhibitor [6] their expression on mast cells encouraged scientists to use pan-TKI for treating mast cells [7].
Masitinib VEGFR-PDGFR inhibitor can inhibit survival and proliferation of cell while Masitinib as FGFR3 inhibitor targets the differentiation and mitogenic properties of cancerous cells. In case of FAK, Masitinib inhibits metastasis.
One can buy Masitinib in the form of a 10 mg vial in $90 for both the laboratory or research purposes. The cost is different from one Masitinib supplier to the other depending upon its purity. Masitinib is poorly soluble in water or ethanol but is soluble in DMSO up to 200 mg/mL. It contains thiazole and pyridine rings in its structure.

ROLE OF MASITINIB IN VETERNARY
Masitinib has been used for a long time for treating a lot of disorders of canines and felines. The use has been extended for the treatment of asthma like diseases in cats and dogs where it acts by inhibiting PDGF-R/c-Kit which in turn inhibits IgE and hence changes ventilation parameters [8]. In feline sarcomas it has shown anti-proliferative and pro-apoptotic activity [9]. Due to c-Kit expression on mast cells, mast cells in canines were also expected to be affected by Masitinib [10] this led to a worthwhile inhibition of mast cells in cats in in vitro model [11].

CLINICAL TRIALS OF MASITINIB
Clinical trials on Masitinib were done on different types of diseases where clinical trials in phase II against both the rheumatoid arthritis [12] and Alzheimer’s disease with a successful adjunct therapy were carried out [13]. Mastocytosis is another area where successful inhibition has been seen and clinical study in phase IIa (NCT00814073) has been carried out [14]. Many other clinical studies related to different diseases has been carried out e.g., asthma [15], solid tumors in phase I clinical trial [16] and gastro-intestinal tumors in phase II trials which described detailed and wide ranging effects on cancer.
The major success of Masitinib was seen against pancreatic cancer where it saw a huge amount of research n trials going on. This small molecule was given as a single anti-cancer agent [17] or combined with Gemcitabine which improved its efficacy [18-19]. Clinical trials on Masitinib on pancreatic cancer patients were successful in phase II clinical studies and were proceeded to phase III [20].

REFERENCES:
1. Demetri, G.D.e.a., Differential Properties of Current Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors. Seminars in Oncology, 2011. 38(1): p. S10-S19.
2. Giamas, G.e.a., Protein kinases as targets for cancer treatment. Pharmacogenomics, 2007. 8(8): p. 1005-1016.
3. Mackenzie, R.e.a., Novel agents for the treatment of adenocarcinoma of the pancreas. Expert Review of Anticancer Therapy, 2009. 9(10): p. 1473-1485.
4. Kelleher, F.C.e.a., Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis, 2011. 32(4): p. 445-451.
5. Philip, P.A.e.a., Novel Targets for Pancreatic Cancer Therapy. Pancreatic Cancer: Current Concepts in Treatment and Research, 2010. 19(2): p. 419-429.
6. Dubreuil, P.e.a., Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT. PLoS One, 2009. 4(9).
7. Pittoni, P.e.a., Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors. Oncogene, 2011. 30: p. 757-769.
8. Guntur, V.P.e.a., The Effect Of Masitinib, A C-kit/PDGF Receptor Tyrosine Kinase Inhibitor, On IgE And Ventilator Parameters In Experimental Feline Asthma. American Journal of Respiratory and Critical Care Medicine.
9. Lawrence, J.e.a., Masitinib demonstrates anti-proliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells. Veterinary and Comparative Oncology, 2011.
10. Hahn, K.A.e.a., Masitinib is Safe and Effective for the Treatment of Canine Mast Cell Tumors. Journal of Veterinary Internal Medicine, 2008. 22(6): p. 1301-1309.
11. Takeuchi, Y.e.a., Biological effect of tyrosine kinase inhibitors on three canine mast cell tumor cell lines with various KIT statuses. Journal of Veterinary Pharmacology and Therapeutics, 2011.
12. Tebib, J.e.a., Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study. Arthritis Research & Therapy, 2009. 11(3).
13. Piette, F.e.a., Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial. Alzheimer's Research & Therapy, 2011. 3(2): p. 16.
14. Paul, C.e.a., Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: A phase 2a study. American Journal of Hematology, 2010. 85(12): p. 921-925.
15. Humbert, M.e.a., Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics. Allergy, 2009. 64(8): p. 1194-1201.
16. Soria, J.C.e.a., Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers. European Journal of Cancer, 2009. 45(13): p. 2333-2341.
17. Cesne, A.L.e.a., Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST). European Journal of Cancer, 2010. 46(8): p. 1344-1351.
18. Mitry, E.e.a., Safety and activity of masitinib in combination with gemcitabine in patients with advanced pancreatic cancer. Cancer Chemotherapy and Pharmacology, 2010. 66(2): p. 395-403.
19. Hammel, P.e.a., Oral tyrosine kinase inhibitor masitinib in combination with gemcitabine in patients with advanced pancreatic cancer: A multicenter phase II study. J Clin Oncol, 2009. 27(15): p. 4617.
20. Chu, E.e.a., Phase III Trials in Pancreatic Cancer in the United States. Clinical Colorectal Cancer, 2010. 9(1): p. 59-60.