The HGF/MET pathway plays an essential physiological role during embryogenesis, and a more restricted role in tissue regeneration and damage repair in healthy adults. In human cancer, the abnormal activation of the MET pathway is well documented. SAR125844 is a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK) with IC50 values of 4.2, 0.22, 1.7, 6.5, 65 and 81 nM for wild-type MET, H1094Y, Y1235D, M1250T, L1195V and D1228H mutants, respectively. SAR125844 demonstrated a potent inhibition of MET phosphorylation with IC50 values of 1.4, 3.9 and 5.1 nM in Hs 746T, SNU-5 and MKN-45 cell lines, respectively. In a panel of 31 tumor cell lines, SAR125844 inhibited cell proliferation in all cell lines with MET gene amplification, with IC50 values in the nanomolar range (1-7 nM). SAR125844 (45 mg/kg) was able to completely inhibit MET kinase in 2 MET-amplified tumor models, with strong impact on downstream MAPK and PI3K pathways. Daily dosing in SNU-5 tumor bearing mice of SAR125844 at 45 mg/kg resulted in complete and almost complete tumor regression in 3/8 mice and 5/8 mice, respectively. SAR125844 (213 mg/kg) was able to maintain a long duration of MET inhibition up to 96h, and induce tumor regression in 2 MET-amplified gastric tumor models without any relevant impact on body weight[3].
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