Selective and Orally Bioavailable c-Met PROTACs for the Treatment of c-Met-Addicted Cancer

c-Met is an attractive therapeutic target in multiple tumors. Previous studies have discovered some effective proteolysis-targeting chimeras (PROTACs) able to degrade c-Met; however, the structure-activity relationship (SAR), degradation selectivity, and pharmacokinetic profiles of c-Met PROTACs have, to date, remained largely unknown. Herein, through extensive SAR studies on various warheads, linkers, and E3 ligase ligands, a novel potent c-Met PROTAC <b>Met-DD4</b> was identified. Our results suggested that <b>Met-DD4</b> could induce robust c-Met degradation with excellent selectivity (DC₅₀ = 6.21 nM), substantially killing the c-Met-addicted cancer cells (IC₅₀ = 4.37 nM). Furthermore, in vivo studies showed that <b>Met-DD4</b> could achieve excellent oral bioavailability and c-Met degradation, strongly retarding tumor growth with minute organ toxicity. Overall, this study reveals that targeted degradation of c-Met is a promising strategy for the treatment of c-Met-addicted cancers and provides novel lead compounds for the clinical translation of c-Met PROTACs.