MK-2461

MK-2461 is a potent inhibitor of c-Met, Ron, Flt1, Flt 3, PDGFRβ, and Mer with IC50 of 2.5 nM, 7 nM, 10 nM, 22 nM, 22 nM, and 24 nM, respectively. MK-2461 also exhibits significant activities toward several other kinases including FGFR1, FGFR2, FGFR3, KDR, TrkA, TrkB, and Flt4 with IC50 of 65 nM, 39 nM, 50 nM, 44 nM, 46 nM, 61 nM, and 78 nM, respectively. MK-2461 preferentially binds to the activated c-Met, and is slightly more potent against five naturally occurring oncogenic human c-Met mutants (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) compared with wild-type c-Met. MK-2461 significantly inhibits constitutive and ligand-induced phosphorylation of the juxtamembrane domain (Y1003) and the COOH-terminal docking site (Y1349/Y1365) of c-Met, as well as phosphorylation of AKT (S473) and ERK1/2 (T202/Y204), without affecting c-Met activation loop (Y1234/35) phosphorylation in GTL-16 cells. MK-2461 displays potent antiproliferative activity against a variety of tumor cell lines with IC50 of 0.1-30 μM. Orally administered MK-2461 inhibits c-Met phosphorylation in vivo, and tumor growth of GTL-16 xenografts, as well as the growth of NIH3T3 tumors harboring murine equivalents of human c-Met Y1230H and M1250T mutants.