Discovery of LAH-1 as potent c-Met inhibitor for the treatment of non-small cell lung cancer

ABSTRCT

Dysregulated HGF/c-Met pathway has been implicated in multiple human cancers and has become an attractive target for cancer intervention. Herein, we report the discovery of N-(3-fluoro-4-((2-(3-hydroxyazetidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (LAH-1), which demonstrated nanomolar MET kinase activity as well as desirable antiproliferative activity, especially against EBC-1 cells. Mechanism studies confirmed the effects of LAH-1 on modulation of HGF/c-Met pathway, induction of cell apoptosis, inhibition on colony formation as well as cell migration and invasion. In addition, LAH-1 also showed desirable in vitro ADME properties as well as acceptable in vivo PK parameters. The design, synthesis, and characterisation of LAH-1 are described herein.

Keywords:

• c-Met
• LAH-1
• antitumor activity
• NSCLC

Disclosure statement

The authors report no conflicts of interest. No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81903472), National-Local Joint Engineering Research Centre for Innovative & Generic Chemical Drug, Guizhou Provincial Natural Science Foundation [No.[2022]4017], National Science Foundation of Health and Family planning Commission of Guizhou Province (gzwkj2022-463), Clinical Medical Technology Innovation Guidance Project of Hunan Provincial Science and Technology Department (2020SK52003).