Novel Highly Potent c‑Met Degraders against a Broad Range of Cancers

The cellular-mesenchymal epithelial transition factor
(c-Met) is
an attractive target in multiple cancers. Despite various c-Met inhibitors
having been developed, the acquired drug resistance hampers their
clinical application. In this study, through elaborately rational
optimization, c-Met degraders, namely, D19, D26, and G4, were developed to exhibit single-digit nanomolar
cell growth inhibition IC50 values, picomolar c-Met degradation
DC50 values, and >99% of maximum degradation in cancer
cells with MET alterations via a Cullin-CRBN-dependent
pathway. Moreover, D19 and G4 showed favorable
pharmacokinetic properties and their oral administration induced complete
EBC-1 xenograft tumor inhibition. Notably, D19 and G4 achieved nanomolar inhibitory activity and degradation
efficacy against tepotinib-resistant cancer cells harboring c-MetD1228N and c-MetY1230H mutations. Furthermore, the
synergetic effects of D19 with epidermal growth factor
receptor/HER2, vascular endothelial growth factor receptor, and BRAF
inhibitors were shown in inhibiting various types of tumor cells.
Overall, this study demonstrates that D19 and G4 serve as promising candidates for the treatment of MET-driven cancers.