SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. (IC50 value of 4.2 nmol/L)

MET RTK:4.2 nM

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.

SAR125844 was preincubated at room temperature with each enzyme for 30 minutes in a buffer containing 10 mmol/L MOPS-NaOH pH 7.0, 0.01% Tween 20, and 1 mmol/L dithiothreitol. The enzymatic reactions were initiated by the addition of a mix of 1 ng/μL of a biotinylated poly(glutamate-alanine-tyrosine) peptide ATP and MgCl2. After 5-minute incubation at room temperature, the reactions were stopped by the addition of anti-phosphotyrosine monoclonal antibody (mAb) PT-66 -Europium cryptate and streptavidin 61SAXLB. After two hours at room temperature, the emission signals at 620 and 665 nm were recorded with a GENios reader, with an excitation wavelength of 320 nm. The percentage of inhibition versus nontreated sample was estimated using the emission ratios at 665/620 nm.

MKN-45, Hs 746T, and SNU-5 cells were seeded in poly d-lysine 96-well plates in complete medium.?Plates were incubated with increasing SAR125844 concentrations for 1 hour, cell lysates were generated using standard procedures and pMETY1230/1234/1235 level evaluated.?IC50 values were calculated using the Biost@t-SPEED internal software and a 4-parameter logistic model

Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844.?Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss.