[CAS NO. 1116743-46-4]  SAR125844

SAR125844 is an ATP-competitive and reversible inhibitor. The biochemical selectivity of SAR125844 is documented in a panel of 275 human kinases and against tubulin. SAR125844 is moderately active on RON, a close structural homolog of MET, with IC50 value of approximately 740 nmol/L, suggesting that SAR125844 is highly (>100-fold) selective for the MET kinase over RON. Minimal inhibitory activity is identified on 5 additional kinases with IC50 values below 300 nmol/L, including TRKA/NTRK1 (39 nmol/L), TRKB/NTRK2 (280 nmol/L), PDGFRα-V561D (55 nmol/L), AXL (87 nmol/L), and MER (105 nmol/L). Biochemical activities on Aurora A and Aurora B are detected with IC50 values of 320 and 820 nmol/L, respectively, but these activities do not translate into cellular activity as demonstrated by the lack of antiproliferative activity in tumor cell lines without MET gene amplification. No activity on tubulin is detected up to 25 μmol/L of SAR125844. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction.