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-Met^D1228N and c-Met^Y1230H 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.