S49076 is a novel and potent inhibitor of MET, AXL/MER, and FGFR1/2/3, effectively blocking cellular phosphorylation of MET, AXL, and FGFRs.

FGFR2:17 nM, MET:1 nM, FGFR2 (N549H):19 nM, FGFR3:15 nM, FGFR1 V561M:23 nM, Axl:7 nM, Mer:2 nM, FGFR1:18 nM

S49076 potently blocks cellular phosphorylation of MET, AXL, and FGFRs, inhibiting downstream signaling both in vitro and in vivo. In cell models, S49076 inhibits proliferation of MET- and FGFR2-dependent gastric cancer cells, blocks MET-driven lung carcinoma cell migration, and inhibits colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. S49076 also inhibits viability, motility, and three-dimensional colony formation of cancer cells expressing MET, AXL, or FGFRs[1].

S49076 shows marked antitumor activity in MET- and FGFR-dependent tumor xenografts at well-tolerated doses. S49076 has high distribution to tumors, in which the half-life for the dose of 3.125 mg/kg is approximately 7 hours versus less than 2 hours in the blood. At doses of 6.25 mg/kg and higher, more than 50% inhibition of MET phosphorylation is retained at 16 hours. S49076 is also active in a bevacizumab-resistant model and totally inhibits the growth of colon carcinoma xenografts in association with bevacizumab[1].

For GTL-16 and SNU-16 viability assays, cells are seeded in 96-well microplates at the appropriate density in media containing 10% FCS and supplemented 48 hours later with serial dilutions of S49076 in a final volume of 150 μL per well. After 96 hours (GTL-16) or 120 hours (SNU-16) incubation, 15 μL of a solution of 5 mg/mL MTT is added to each well and the plates are incubated for 4 hours at 37℃. The formazan metabolite is solubilized in SDS for SNU-16 and, following removal of the MTT solution, in DMSO for GTL-16. Global cell viability is estimated by measurement of optical density at 540 nm. (Only for Reference)