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, <b>D19</b>, <b>D26</b>, and <b>G4</b>, 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 <i>MET</i> alterations via a Cullin-CRBN-dependent pathway. Moreover, <b>D19</b> and <b>G4</b> showed favorable pharmacokinetic properties and their oral administration induced complete EBC-1 xenograft tumor inhibition. Notably, <b>D19</b> and <b>G4</b> 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 <b>D19</b> 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 <b>D19</b> and <b>G4</b> serve as promising candidates for the treatment of <i>MET</i>-driven cancers.