SAR125844

SAR125844 is a potent, selective, and ATP-competitive MET kinase inhibitor with the value of IC50 is 4.2 nM and Ki is 2.8 nM. SAR125844 has antitumor activity and can be used for the research of cancer[1][2][3].

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.

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 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).

c-Met

[1] Egile C, et al. The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer [J]. Molecular cancer therapeutics, 2015, 14(2): 384-394. DOI:10.1158/1535-7163.MCT-14-0428
[2] Angevin E, et al. A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification [J]. European Journal of Cancer, 2017, 87: 131-139. DOI:10.1016/j.ejca.2017.10.016
[3] Ugolini A, et al. Discovery and pharmacokinetic and pharmacological properties of the potent and selective MET kinase inhibitor 1-{6-[6-(4-fluorophenyl)-[1, 2, 4] triazolo [4, 3-b] pyridazin-3-ylsulfanyl] benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl) urea (SAR125844) [J]. 2016. DOI:10.1021/acs.jmedchem.6b00280
[4] Egile C, et al. The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. Mol Cancer Ther. 2015 Feb;14(2):384-94. DOI:10.1158/1535-7163.MCT-14-0428