Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT

Abstract

BackgroundThe stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT.Methodology/Principal Findings In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200±40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150±80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant.ConclusionsMasitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity.

Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice

“…49 However, the half-life of the drug is very short, and no durable and meaningful clinical responses were observed in clinical studies in AdvSM (Table 1). 50 Masitinib: Masitinib, which inhibits KIT WT and LYN, 51 is an effective drug for canine MC tumors. 52 However, in humans, the KIT D816V mutation introduces resistance against masitinib.…”

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

“…3) Masatinib mesilate (AB1010) has been shown to inhibit human and murine KIT with juxtamembrane activating KIT mutations, as well as PDGFRA-a/b, and Lyn kinases at nanomolar concentrations in cell-based assays [122]. In contrast, masatinib only weakly inhibited KITD816V-driven cell proliferation (micromolar concentrations).…”

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

“…Dasatinib (Sprycel, Bristol-Myers Squibb, New York, NY, USA) , midostaurin (PKC412, Novartis) (Gleixner et al, 2006) and EXEL-0862 (Exelixis, San Francisco, CA, USA) (Pan et al, 2007) have been shown to inhibit D816V mutants, and clinical trials of midostaurin and dasatinib are currently going on in patients with aggressive SM and MC leukemia. In preclinical trials, masitinib (AB Science, Paris, France) proved to be the most specific inhibitor of c-Kit among TKIs (Dubreuil et al, 2009).…”