Pamufetinib (TAS-115) is a potent kinase inhibitor targeting VEGFR and the hepatocyte growth factor receptor (c-Met/HGFR), with IC50s of 30 nM for rVEGFR2 and 32 nM for rMET, respectively.

c-Met:32 nM, VEGFR2:30 nM

pamufetinib is ATP antagonism(Ki of 12 and 39 nM for rVEGFR2 and rMET, respectively). Like other known VEGFR or MET inhibitors, AS-115 strongly inhibits the kinase activity of VEGFR2 and MET and their signal-dependent cell growth. TAS-115 induces less damage in various normal cells than do other VEGFR inhibitors[1]. TAS-115 does not affect the growth of PC-9 or HCC827 cells at concentrations less than 10 μM; however, the combined use of TAS-115 with erlotinib reverses HGF-induced resistance in the cell lines in a concentration-dependent manner. VEGF production by cancer cells and endothelial proliferation inhibited by TAS-115[2].

During the treatment period,pamufetinib (50 mg/kg/d) completely prevents tumor growth. In MET-amplified human cancer transplanted models,pamufetinib (200 mg/kg/d) induces a 48% regression from the initial tumor volume . ED50 of Tpamufetinib in this model is 8 mg/kg/d. Pamufetinib significantly prolongs survival of these mice when administered at doses of 50 or 200 mg/kg/d[1]. Pamufetinib inhibits angiogenesis in PC-9/HGF tumors in vivo. Moreover, the doublet erlotinib and pamufetinib successfully inhibit PC-9/HGF tumor growth and delay tumor regrowth associated with sustained tumor vasculature inhibition even after cessation of the treatment[2].