A New Small-molecule Type C-Met Kinase Inhibitors Effects In Vivo And In Vitro Studies

In our study,we firstly use HTRF?Homogeneous Time-Resolved Fluorescence?technology to find that the IC₅₀ of Cpd1405 in c-Met kinase is 0.34 nM.Then the IC₅₀ of compound Cpd1405 in SNU-5 cells and H1993 cells are 2.02 nM and 2.02 nM.Using LC-MS/MS,in different species?human,rat,monkey?liver microsomal enzymes,compound Cpd1405 has no direct inhibition and time-dependent inhibition.The half-life(t_1/2)and bioavailability are 229.55+/-21.32min and 14.71%respectively in rats.In the SNU-5 tumor model,we use the athymic nude mice to test the inhibition of Cpd1405.In the 0.3 mg/kg,1 mg/kg,3 mg/kg and 10 mg/kg test,four dose groups all show good antitumor activity?tumor inhibition rates were 60.38%,60.38%,74.54%,82%respectively?,obviously better than or equivalent to the INCB28060 compound.In a word,with excellent properties in pharmacodynamics and pharmacokinetics,compound Cpd1405 has been selected as a preclinical candidate for further anticancer drug development.