Vatalanib

A potent, orally available class III receptor tyrosine kinases inhibitor with IC50 of <1 uM for VEGFR, Flt-1, KDR and PDGFRβ; shows no activity against EGFR, FGFR-1, c-Met, and Tie-2, or c-Src, c-Abl, and PKC-α; blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor with IC50 of 34 nM; inhibits EGF and PDGF-induced angiogenesis in a growth factor implant model (25-100 mg/kg) .Ovarian Cancer Phase 1 Discontinued (In Vitro) :Vatalanib also inhibits Flk, c-Kit and PDGFRβ with IC50 of 270 nM, 730 nM and 580 nM, respectively. Vatalanib shows the anti-proliferation effect by inhibiting thymidine incorporation induced by VEGF in HUVECs with and IC50 of 7.1 nM, and dose-dependently suppresses VEGF-induced survival and migration of endothelial cells in the same dose range without cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. A recent study shows that Vatalanib significantly inhibits the growth of hepatocellular carcinoma cells and enhances the IFN/5-FU induced apoptosis by increasing proteins levels of Bax and reduced Bcl-xL and Bcl-2. (In Vivo) :Vatalanib induces dose-dependent inhibition of the angiogenic response to VEGF and PDGF in both a growth factor implant model and a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg) . In the same dose range, Vatalanib also inhibits the growth and metastasesof several human carcinomas in nude mice without significant effect on circulating blood cells or bone marrow leukocytes.