Savolitinib is a novel triazolopyrazine-based c-Met inhibitor with IC50 values of 5nM, 3nM and 6nM for inhibition of c-Met enzyme, HGF-mediated c-Met phosphorylation and HGF-induced proliferation assay in NCI-H441 cell line, respectively. Single oral dose of 3 mg/kg Savolitinib achieved inhibition of HGF-mediated c-Met phosphorylation by 84.7% at 6h post administration in mice. Oral dose of savolitinib at 1, 2.5 and 10mg/kg once daily for 21 days dose-dependently inhibited tumor growth in U87MG subcutaneous xenograft athymic nude mice model[1]. The MET D1228 site is important for Savolitinib, for the MET D1228V mutation could induce resistance to type I MET inhibitor like savolitinib[2].
作用机制
Savolitinib can bind to c-Met in a unique mode including wrapping around Met1211 c-Met in a“U-shaped” conformation. It also binds to the activation loop through Asp1228 and Lys1110 residues.[1][2]
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