Discovery of Potent and Selective c‑Met Degraders for Hepatocellular Carcinoma Treatment

Targeting c-Met is a clinical trend for the precise treatment
of
HCC, but the potential issue of acquired drug resistance cannot be
ignored. Targeted protein degradation technology has demonstrated
promising prospects in disease treatment and overcoming drug resistance
due to its special mechanism of action. In this study, we designed
and synthesized two series of novel c-Met degraders and conducted
a systematic biological evaluation of the optimal compound H11. H11 exhibited good c-Met degradation activity and
anti-HCC activity. Importantly, H11 also demonstrated
more potent inhibitory activity against Ba/F3-TPR-MET-D1228N and Ba/F3-TPR-MET-Y1230H
cell lines than did tepotinib. In summary, H11 displayed
potent anti-HCC activity as a degrader and may overcome resistance
to type Ib inhibitors, making it a new therapeutic strategy for HCC
with MET alterations.