PHA-665752

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor, have been implicated in the development and progression of several human cancers. PHA 665752 is an ATP-competitive, active-site inhibitor of the catalytic activity of c-Met kinase (Ki = 4 nM; IC50 = 9 nM). It exhibits >50-fold selectivity for c-Met over a panel of tyrosine and serine/threonine kinases. PHA 665752 can inhibit c-Met phosphorylation, as well as cell proliferation and cell motility, of various tumor cells (IC50s = 18-50 nM). It also inhibits signal transduction downstream of c-Met, interfering with the activation of Gab-1 adaptor protein, ERK1/2, Akt, STAT3, PLC-γ, and focal adhesion kinase in multiple tumor cell lines. In a gastric carcinoma xenograft model, 25 mg/kg PHA-665752 was shown to reduce tumor growth in mice by inhibiting c-Met activation.