Merestinib dihydrochloride is an effective and orally bioavailable c-Met inhibitor (Ki=2 nM). It has anti-tumor activities and also has potent activity against MST1R (IC50=11 nM), FLT3 (IC50=7 nM), AXL (IC50=2 nM), MERTK (IC50=10 nM), TEK (IC50=63 nM), ROS1, DDR1/2 (IC50=0.1/7 nM) and MKNK1/2 (IC50=7 nM).

TEK:63 nM, MerTK:10 nM, FLT3:7 nM, MST1R:11 nM, MKNK1/2:7 nM, DDR1/2:0.1/7 nM, c-Met:(ki)2 nM, Axl:2 nM

Merestinib demonstrates the effects on MET pathway-dependent cell scattering and cell proliferation. The mean IC50 value (n=6 determinations) of Merestinib for inhibition of MET auto-phosphorylation in HGF-stimulated H460 cells is 35.2±6.9 nM and the IC50 for MET auto-phosphorylation in S114 cells is 59.2 nM. Merestinib also inhibits MST1R (IC50=11 nM), AXL (IC50=2 nM), MERTK (IC50=10 nM), TYRO3 (IC50=28 nM), ROS1, PDGFRA (IC50=41 nM), FLT3 (IC50=7 nM), TEK (IC50=63 nM), DDR1/2 (IC50=0.1/7 nM) and MKNK1/2 (IC50=7 nM)[1]. Merestinib (2, 5, and 10 μM) decreases the number of viable TFK-1 and SZ-1 cells in a dose and time-dependent manner, and significant inhibits wound healing for TFK-1 and SZ-1 cell lines. Transfection with the MET variants confers growth-factor independence and treatment with Merestinib inhibits the growth of these MET variant clones with an IC50 ranging from 3-fold more potent (V1092I) to approximately 6-fold less potent (L1195V) compare with the growth inhibition of cells with the MET wild-type sequence[1]. Merestinib inhibits cell invasion in TFK-1 and SZ-1 cells in a concentration-dependent manner[2].

Merestinib is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a pharmacodynamic residence time (Koff) of 0.00132 min-1 and t1/2 of 525 min. Merestinib (20 mg/kg) decreases TFK-1 tumor growth significantly relative to vehicle control. Merestinib treatment inhibits MET phosphorylation with a composite TED50 (50 % target inhibition dose) of 1.2 mg/kg and a composite TED90 (90 % target inhibition dose) of 7.4 mg/kg[1]. Merestinib inhibits the growth of intra- and extrahepatic CCC xenograft tumors[2]. Merestinib demonstrates anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4), and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects.