MK-2461

MK-2461 is an ATP-competitive, selective and orally active wild-type and mutant c-Met inhibitor (IC₅₀s: 0.4-2.5 nM). MK-2461 also inhibits Ron (IC₅₀ of 7 nM) and Flt1 (IC₅₀ of 10 nM), MK-2461 shows selective for c-MET over other kinases (lC₅₀s = 22-7800 nM). MK-2461 can be used for the study of cancer, such as gastric cancer^[1]. In Vitro:MK-2461 (0.61-10000 nM; 2 h) inhibits the phosphorylation of the juxtamembrane domain (Y1003) and the COOH-terminal docking site (Y1349/Y1365) of c-Met and phosphorylation of AKT (S473) and ERK1/2 (T202/Y204)^[1].
MK-2461 is substantially more potent against the autophosphorylation of Y1349 (IC₅₀ of ~100 nM) and Y1365 (IC₅₀ of ~26 nM) in the COOH-terminal docking site than the autophosphorylation of the activation loop (IC₅₀ of ~900 nM)^[1].
MK-2461 potently inhibits the phosphorylation of three nonactivation loop tyrosine residues of c-Met, Y1003 in the juxtamembrane domain and Y1349 and Y1365 in the COOH-terminal docking site (IC₅₀ of ~50 nM). MK-2461 also inhibits the phosphorylation of AKT (S473) and ERK1/2 (T202/Y204). In contrast, MK-2461 has little effect on c-Met activation loop (Y1234/Y1235) phosphorylation^[1].
In the presence of 50 μM ATP (HY-B2176), MK-2461 is equally or more potent against the five mutants (Y1230C, Y1230H, Y1235D, M1250T, and N1100Y) (mean IC₅₀ ranging from 0.4 to 1.5 nM) compared with the wild-type c-Met (mean IC₅₀ = 2.5 nM)^[1].
MK-2461 potently inhibits phosphorylation of the activation loop of FGFR2 (Y653/Y654) and PDGFR-α (Y849) in KATO III cells with IC₅₀ <300 nM^[1].
MK-2461 inhibits HGF-induced mitogenesis of 4MBr-5 monkey lung epithelial cells and HPAF II cells with IC₅₀s of 204 nM and 416 nM, respectively^[1].
MK-2461 potently inhibits IL-3-independent growth of 32D/Tpr-Met and 32D/Tpr-Met (Y362C) cells (IC₅₀ of ~100 nM)^[1].
In Vivo:MK-2461 (100 mg/kg; oral gavage; twice daily or once daily; for 21 days) effectively suppresses c-Met signaling and tumor growth in a murine xenograft model of c-Met-dependent gastric cancer^[1].
MK-2461 (134 mg/kg; oral gavage; twice daily; for 21 days) inhibits tumor growth in a model of tumors formed by s.c. injection of mouse NIH-3T3 cells expressing oncogenic c-Met mutants^[1].