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 Met-DD4 was
identified. Our results suggested that Met-DD4 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 Met-DD4 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.