Uses
S49076 is a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3 with IC50 values below 20 nM.
Biological Activity
S49076 is a novel and potent inhibitor of Met (c-Met), AXL/MER and FGFR1/2/3 with IC50 below 20 nM.
in vivo
S49076 effectively inhibits the phosphorylation of MET, AXL and FGFRs in cells, and inhibits their downstream signaling pathways in vitro and in vivo. In cellular models, it inhibits MET and FGFR2-dependent gastric cancer cells, prevents MET-driven migration of lung cancer cells, and inhibits colony formation of liver cancer cells expressing FGFR1/2 and AXL. S49076 inhibits cell viability, motile, three-dimensional colony formation of cancer cells expressing MET, AXL or FGFRs.
in vivo
S49076 has significant antitumor activity in MET- and FGFR-dependent tumor grafts. It is highly distributed in tumors, with a half-life of approximately 7 hours in tumors and less than 2 hours in blood at a dose of 3.125 mg/kg. At doses above 6.25 mg/kg, more than 50% of MET phosphorylation was inhibited for 16 hours. S49076 was also active in a bevacizumab-resistant model, and in combination with bevacizumab, completely inhibited the growth of colon cancer xenografts.
target
| Target | Value |
Met
(Cell-free assay) | 1 nM |
Mer
(Cell-free assay) | 2 nM |
< td style="border-bottom: 1px dotted #ccc;padding: 5px;"> Axl
(Cell-free assay) 7 nM |
FGFR3
(Cell-free assay) | 15 nM |
FGFR2
(Cell-free assay) | 17 nM |
IC 50
FGFR1: 18 nM (IC
50); FGFR1
V561M: 23 nM (IC
50); FGFR2: 17 nM (IC
50); FGFR2
N549H: 19 nM (IC
50); FGFR3: 15 nM (IC
50); AXL: 7 nM (IC
50); MER: 2 nM (IC
50)
References
[1] Burbridge MF, et al. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. Mol Cancer Ther. 2013 Sep;12(9):1749-62. DOI:
10.1158/1535-7163.MCT-13-0075
