Merestinib (LY2801653)

LY2801653 demonstrates in vitro effects on MET pathway-dependent cell scattering and cell proliferation. It demonstrates more potent anti-proliferative activity in cell lines with MET gene amplification (MKN45, Hs746T and H1993) than the cell lines without MET gene amplification (U-87MG, KATO-III). LY2801653 also maintains potency against 13 MET variants, each bearing a single-point mutation. It is found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The mean IC50 value of LY2801653 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^[1].

2×10³ DU145 cells/well on poly-D-lysine 96-well black/clear plates are treated with LY2801653 (in 0.4 % DMSO), immediately followed by the addition of human HGF (20 ng/ml), and incubated for 48 h at 37 °C. 2 % formaldehyde fixed cells are stained with AlexaFluor 488 Phalloidin and counterstained with Propidium Iodide. Colony counts are quantified on Acumen Explorer™ laser-scanning fluorescence microplate cytometer. A colony is defined as≥4 cells.

LY2801653 shows in vivo 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. It is able to induce vessel normalization in xenograft tumors. Among the species studied, LY2801653 has the shortest elimination half life in mice of 2.9 h, compared with 14.3 h in non-human primate. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer^[1].