PF-04217903

PF-04217903 is a potent, selective, ATP-competitive c-Met kinase inhibitor with Ki of 4.8 nM, inhibits HGF-stimulated tyrosine phosphorylation of wild type c-Met with IC50 of 7.3 nM in cell-based assays; shows similar potency for inhibition of c-Met phosphorylation in mIMCD3 mouse epithelial cells (IC50=6.9 nM) and MDCK cell (IC50=9.5 nM) ; also exhibits inhibitory activities against c-Met mutations including V1092I, H1094R, M1250T, R988C, and T11010I (IC50=530 nM), but has little to no activity against mutants Y1230C and Y1235D; inhibits tumor cell proliferation, survival, migration/invasion both in vitro and in vivo.Solid Tumors Phase 1 Discontinued (In Vitro) :PF-04217903 (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.PF-04217903 (1.5-3333 nM; 48 hours) induces apoptosis of GTL-16 cells (IC50=31 nM) .PF-04217903 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) . PF-04217903 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. (In Vivo) :PF-04217903 (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.PF-04217903 (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 phenolsulfonate 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 strongly induces phospho-PDGFRβ levels in U87MG xenograft tumors.