MK-2461, a Novel Multitargeted Kinase Inhibitor, Preferentially Inhibits the Activated c-Met Receptor

Abstract

The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer.

ARQ 197, a Novel and Selective Inhibitor of the Human c-Met Receptor Tyrosine Kinase with Antitumor Activity

“…S1). This feature of ARQ 197 distinguishes it from all the publicly disclosed c-Met inhibitors in clinical and preclinical development, most of which have been reported to be ATP competitive (37,38). Although a K i value of 355 nmol/L suggests that ARQ 197 is not as potent as other c-Met inhibitors under development, the pharmacokinetic suppression, pathway inhibition, and antiproliferative effects in cellular assays are in the same range as the biochemical potency, differentiating it from what is typically obtained for an ATP-competitive inhibitor.…”

Early Clinical Development of ARQ 197, a Selective, Non–ATP-Competitive Inhibitor Targeting MET Tyrosine Kinase for the Treatment of Advanced Cancers

“…ARQ 197 binds to an inactive, or nonphosphorylated, conformation of MET and locks it in this inactive state [20]. Kinetic analyses of ARQ 197 demonstrate high in vitro potency (inhibitory constant [K i ] Ϸ 35.5 nM) and a non-ATP-competitive mechanism of action, which may explain a high degree of kinase selectivity that distinguishes the compound from other MET inhibitors [18,21,22]. ARQ 197 inhibits both constitutive and ligandmediated MET autophosphorylation in different human cancer cell lines, with a 50% inhibitory concentration (IC50) of 100 -300 nM (Table 1), in turn inhibiting downstream MET effectors Akt, Erk-1/2, and STAT-3 [18].…”

Structural Basis for Selective Small Molecule Kinase Inhibition of Activated c-Met

“…The clinical candidate MK-2461 is a novel, receptor tyrosine kinase inhibitor (3,9). MK-2461 preferentially binds the phosphorylated c-Met kinase domain in vitro and preferentially inhibits phosphorylated c-Met in cancer cell lines (9).…”