PF-04217903 (mesylate)

PF-04217903 mesylate is a potent ATP-competitive c-Met kinase inhibitor with K_i of 4.8 nM for human c-Met. PF-04217903 mesylate shows more than 1,000-fold selectivity relative to 208 kinases. Antiangiogenic properties^[1][2]. IC50 & Target:Ki: 4.8 nM (human c-Met)^[1] In Vitro:PF-04217903 mesylate (0.1-10000 nM; 48-72 hours) inhibits proliferation of c-Met–amplified human GTL-16 gastric carcinoma and H1993 NSCLC cells with IC₅₀ values of 12 and 30 nM, respectively^[1].
PF-04217903 mesylate induces apoptosis of GTL-16 cells (IC₅₀=31 nM) ^[1].
PF-04217903 mesylate also inhibits HGF-mediated cell migration and Matrigel invasion in several c-Met–overexpressing tumor cell lines such as human NCI-H441 lung carcinoma and HT29 colon carcinoma with IC50 values comparable with those for inhibition of c-Met phosphorylation in these cell lines (IC₅₀= 7-12.5 nM)^[1].
PF-04217903 mesylate displays similar potency to inhibit the activity of c-Met-H1094R, c-Met-R988C, and c-Met-T1010I with IC₅₀ of 3.1 nM, 6.4 nM, and 6.7 nM, respectively, but has no inhibitory activity against c-Met-Y1230C with IC₅₀ of >10 μM^[3]. In Vivo:PF-04217903 mesylate (1-30 mg/kg; p.o.; daily for 16 days) shows dose-dependent tumor growth inhibition, which correlated with the inhibition in c-Met phosphorylation in these tumors ^[1].
PF-04217903 mesylate (5-50 mg/kg, p.o.; once daily for 3 days) dose dependently inhibits c-Met, Gab-1, Erk1/2, and AKT phosphorylation and induced apoptosis (cleaved caspase-3) in U87MG xenograft tumors at all dose levels. PF-04217903 mesylate shows a significant dose-dependent reduction of human IL-8 levels in both the U87MG and GTL-16 models and decreases human VEGFA levels in the GTL-16 model. PF-04217903 mesylate strongly induces phospho-PDGFRβ levels in U87MG xenograft tumors^[1].