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

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.