Rational Design, Synthesis, and Biological Evaluation of Novel c-Met Degraders for Lung Cancer Therapy

Abstract

Cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target for treating multiple cancers. Despite plentiful c-Met inhibitors have been developed, some issues, including the acquired drug resistance to c-Met inhibitors, have emerged to hamper their application in clinical treatment. Degradation of c-Met offers an opportunity to solve these issues. In this study, we developed a series of c-Met degraders, and the optimal compound 22b can efficiently degrade c-Met with a DC₅₀ value of 0.59 nM in EBC-1 cells. Mechanistic studies revealed that compound 22b induced c-Met degradation via proteasome-mediated pathway. In addition, compound 22b suppressed the proliferation and also induced apoptosis of EBC-1 cells, outperforming the corresponding inhibitor tepotinib. Importantly, compound 22b showed favorable pharmacokinetic properties and significantly induced tumor regression in a xenograft model without obvious toxicity. In brief, this study provided compound 22b as a novel c-Met degrader for lung cancer therapy.