Discovery of N-(4-(pyridin-4-yloxy)phenyl)-1,2-dihydropyridine-3-carboxamide derivatives as potential type II c-Met inhibitors.

The c-Met receptor tyrosine kinase plays a pivotal role in oncogenesis and tumor progression, with its dysregulation frequently contributing to therapeutic resistance. Through structure-based virtual screening of the ChemDiv database, we prioritized 20 candidates, including type II and III inhibitors, with compounds A3 and A17 emerging as initial hits. Subsequent optimization yielded A30, a hybrid scaffold inhibitor demonstrating potent activity against both wild-type and mutant c-Met, comparable to the reference inhibitor BMS-777607. Cellular assays revealed that A30 significantly suppressed proliferation, migration, and colony formation in NCI-H1993 and HCT-116 cells, while inducing apoptosis. These findings highlight A30 as a promising lead compound for targeting c-Met-driven resistance.