Biological Activity
SAR125844 is a potent and highly selective Met (c-Met) kinase inhibitor with nanomolar activity against wild-type Met (c-Met) kinase (IC50=4.2 nM), against H1094Y, Y1235D, M1250T, The IC50s of the L1195V and D1228H mutants were 0.22, 1.7, 6.5, 65 and 81 nM, respectively.
in vitro
SAR125844 is an ATP-competitive and reversible inhibitor. SAR125844 has moderate activity against RON, a homolog that is structurally similar to MET, and SAR125844 inhibits RON with an IC50 of approximately 740 nM. SAR125844 is more than 100-fold more selective for MET kinase than for RON.
in vivo
In a pharmacokinetic study in mice, the oral bioavailability of SAR125844 was low, approximately 2%. Its Caco-2 permeability is moderate. In female SCID mice bearing xenograft tumors (inoculated with the MET-expanded Hs 746T human gastric tumor cell line), a single intravenous injection of 20 mg/kg of SAR125844 resulted in a plasma exposure of 6190 h ng/kg mL, clearance CL = 3.1 L/h/kg, large volume of distribution (Vss = 4.2 L/kg).
