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在纳摩尔范围内，通过细胞实验抑制MET自磷酸化作用，并且在具有MET基因扩增或路径依赖的细胞系中，以低纳摩尔浓度选择性促进凋亡和抗增殖活性。

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.