Merestinib dihydrochloride

Merestinib dihydrochloride (LY2801653 dihydrochloride) is a potent, orally bioavailable c-Met inhibitor (K_i=2 nM) with anti-tumor activities. Merestinib dihydrochloride 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)^[1][2]. IC50 & Target: Ki: 2 nM (c-Met)^[1]
IC50: 11 nM (MST1R), 7 nM (FLT3), 2 nM (AXL), 10 nM (MERTK), 63 nM (TEK), 0.1/7 nM (DDR1/2), 7 nM (MKNK1/2)^[1] In Vitro: Merestinib (LY2801653) 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 demonstrates 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. Transfection with the MET variants confers growth-factor independence and treatment with Merestinib inhibits 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 (2, 5, and 10 μM) reduces 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. Merestinib inhibits cell invasion in TFK-1 and SZ-1 cells in a concentration dependent manner^[2]. In Vivo: Merestinib (LY2801653) 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. Merestinib (LY2801653) is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a pharmacodynamic residence time (K_off) of 0.00132 min^-1 and t_1/2 of 525 min. Merestinib (LY2801653) 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 (LY2801653) (20 mg/kg) reduces TFK-1 tumor growth significantly relative to vehicle control. Merestinib (LY2801653) inhibits the growth of intra- and extrahepatic CCC xenograft tumors^[2].