Masitinib mesylate (AB-1010 mesylate) is a potent, orally bioavailable, and selective inhibitor of c-Kit ( IC 50 =200 nM for human recombinant c-Kit). It also inhibits PDGFRα/β ( IC 50 s=540/800 nM), Lyn ( IC 50 = 510 nM for LynB), Lck , and, to a lesser extent, FGFR3 and FAK . Masitinib mesylate (AB-1010 mesylate) has anti-proliferative, pro-apoptotic activity and low toxicity.
In Vitro
Masitinib is a competitive inhibitor against ATP at concentrations ≤500 nM. Masitinib also potently inhibits recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. Masitinib demonstrates weak inhibition of Abl and c-Fms. Masitinib more strongly inhibits degranulation, cytokine production, and bone marrow mast cell migration than imatinib. In Ba/F3 cells expressing human wild-type Kit, masitinib inhibits SCF (stem cell factor)-induced cell proliferation with an IC 50 of 150 nM, while the IC 50 for inhibition of IL-3-stimulated proliferation is at approximately >10 μM. In Ba/F3 cells expressing PDGFRα, masitinib inhibits PDGF-BB-stimulated proliferation and PDGFRα tyrosine phosphorylation with IC 50 of 300 nM. Masitinib also causes inhibition of SCF-stimulated tyrosine phosphorylation of human Kit in mastocytoma cell-lines and BMMC. Masitinib inhibits Kit gain-of-function mutants, including V559D mutant and Δ27 mouse mutant with IC 50 of 3 and 5 nM in Ba/F3 cells. Masitinib inhibits the cell proliferation of mastocytoma cell lines including HMC-1α155 and FMA3 with IC 50 of 10 and 30 nM, respectively. ?\nMasitinib inhibits cell growth and PDGFR phosphorylation in two novel ISS cell lines, which suggest that Masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
Masitinib inhibits tumour growth and increases the median survival time in Δ27-expressing Ba/F3 tumor models at 30 mg/kg, without cardiotoxicity or genotoxicity . ?\nMasitinib (12.5 mg/kg/d, p.o.) increases overall TTP (time-to-tumor progression) compared with placebo in dogs. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
