Discovery of quinoline-based derivatives as c-Met inhibitors for the treatment of non-small cell lung cancer.

Abstract

The clinical utility of type II mesenchymal-epithelial transition factor (c-Met) inhibitors remains constrained by narrow therapeutic windows and dose-limiting toxicities, underscoring an urgent need for structurally differentiated candidates with improved developability. Herein, we report the design, synthesis, and biological evaluation of a novel series of type II c-Met inhibitors bearing α-amino acid-derived linkers and a morpholinopropoxy quinoline scaffold. Systematic structure-activity relationship studies identified compound 41 as the most potent analogue, exhibiting an IC50 of 18 nM against c-Met kinase and 120 nM against MET-amplified EBC-1 cells, with marked selectivity over non-MET-addicted cell lines. Kinase selectivity profiling revealed that compound 41 displayed dramatically improved selectivity over cabozantinib against the clinically relevant off-targets AXL, FLT3, and RON. Mechanistically, compound 41 abrogated c-Met autophosphorylation and its downstream cascades, concomitantly inducing apoptotic cell death and suppressing both migratory and invasive phenotypes at nanomolar concentrations. Pharmacokinetic (PK) evaluation in Sprague-Dawley rats demonstrated an absolute oral bioavailability of 38.0% with adequate systemic exposure. In an EBC-1 xenograft model, oral administration of compound 41 (30 mg/kg/d) produced robust tumor growth inhibition (TGI = 82.2%) comparable to cabozantinib (10 mg/kg/d), with no significant body weight loss and no apparent histopathological abnormalities in major organs. Collectively, these findings position compound 41 as a promising lead for the development of next-generation, tolerable c-Met targeted therapeutics.