Selective and\nOrally Bioavailable c‑Met PROTACs\nfor the Treatment of c‑Met-Addicted Cancer

c-Met is an attractive therapeutic target in multiple\ntumors. Previous\nstudies have discovered some effective proteolysis-targeting chimeras\n(PROTACs) able to degrade c-Met; however, the structure–activity\nrelationship (SAR), degradation selectivity, and pharmacokinetic profiles\nof c-Met PROTACs have, to date, remained largely unknown. Herein,\nthrough extensive SAR studies on various warheads, linkers, and E3\nligase ligands, a novel potent c-Met PROTAC <b>Met-DD4</b> was\nidentified. Our results suggested that <b>Met-DD4</b> could\ninduce robust c-Met degradation with excellent selectivity (DC<sub>50</sub> = 6.21 nM), substantially killing the c-Met-addicted cancer\ncells (IC<sub>50</sub> = 4.37 nM). Furthermore, in vivo studies showed\nthat <b>Met-DD4</b> could achieve excellent oral bioavailability\nand c-Met degradation, strongly retarding tumor growth with minute\norgan toxicity. Overall, this study reveals that targeted degradation\nof c-Met is a promising strategy for the treatment of c-Met-addicted\ncancers and provides novel lead compounds for the clinical translation\nof c-Met PROTACs.