[CAS NO. 905854-02-6]  Tivantinib (ARQ 197)

ARQ-197 has been shown to prevent HGF/c-met induced cellular responses in vitro. ARQ-197 possesses antitumor activity; inhibiting proliferation of A549, DBTRG and NCI-H441 cells with IC50 of 0.38, 0.45, 0.29 μM. Treatment with ARQ-197 results in a decrease in phosphorylation of the MAPK signaling cascade and prevention of invasion and migration. In addition, ectopic expression of c-Met in NCI-H661, a cell line having no endogenous expression of c-Met, causes it to acquire an invasive phenotype that is also suppressed by ARQ-197. Although the addition of increasing concentrations of ARQ-197 does not significantly affect the K of ATP, exposure of c-Met to 0.5 μM ARQ-197 decreased the V of c-Met by approximately 3-fold. The ability of ARQ-197 to decrease the V without affecting the Km of ATP confirmed that ARQ-197 inhibits c-Met through a non–ATP-competitive mechanism and may therefore account for its high degree of kinase selectivity. ARQ-197 prevents human recombinant c-Met with a calculated inhibitory constant K of approximately 355 nM. Although the highest concentration of ATP used is 200 μM, the potency of ARQ-197 against c-Met is not reduced by using concentrations of ATP up to 1 mM. ARQ-197 blocks c-Met phosphorylation and downstream c-Met signaling pathways. ARQ-197 suppresses constitutive and ligand-mediated c-Met autophosphorylation and, by extension, c-Met activity, in turn leading to the inhibition of downstream c-Met effectors. ARQ-197 induction of caspase-dependent apoptosis is increased in c-Met–expressing human cancer cells including HT29, MKN-45, and MDA-MB-231 cells.