LY2801653 is an orally bioavailable MET kinase inhibitor (Ki = 2 nM). It also inhibits MST1R, Axl, MNK1/2, FLT3, DDR1, and DDR2 (IC50s = 11, 2, 7, 7, 0.1, and 7 nM, respectively, in a cell-based assay). It inhibits MET autophosphorylation stimulated by hepatocyte growth factor (HGF) in H460 and S114 cells (IC50s = 35.2 and 59.2 nM, respectively) and inhibits growth of Ba/F3 cells transfected with MET-activating mutations (IC50s = 12-248 nM). LY2801653 (0.01-10 μM) completely blocks cell scattering induced by HGF in DU145 cells. It reduces tumor growth in MET autocrine (U-87MG) and MET over-expression (H441) mouse xenograft models when administered at doses of 4 and 12 mg/kg.
MET is a tyrosine kinase that leads to downstream activation of several pathways
including RAS and MAPK.?As a result, it is quite possible that MET inhibition can
be active in RAS mutant tumors and maybe associated with EGFR resistance in
NSCLC.?Two MET inhibitors, tivantinib and onartuzumab, have been examined in
KRAS mutant NSCLC with others in clinical trials at this time.
Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, and NTRK1/2/3.
[1] yan s b et al. , ly2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against met, mst1r, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. invest new drugs. 2012, 31: 833-844.
