Expanding the Chemistry of Dihaloacetamides as Tunable Electrophiles for Reversible Covalent Targeting of Cysteines

摘要

The choice of an appropriate electrophile is crucialin the designof targeted covalent inhibitors (TCIs). In this report, we systematicallyinvestigated the glutathione (GSH) reactivity of various haloacetamidesand the aqueous stability of their thiol adducts. Our findings revealedthat dihaloacetamides cover a broad range of GSH reactivity dependingon the combination of the halogen atoms and the structure of the aminescaffold. Among the dihaloacetamides, dichloroacetamide (DCA) exhibitedslightly lower GSH reactivity than chlorofluoroacetamide (CFA). TheDCA-thiol adduct is readily hydrolyzed under aqueous conditions,but it can stably exist in the solvent-sequestered binding pocketof the protein. These reactivity profiles of DCA were successfullyexploited in the design of TCIs targeting noncatalytic cysteines ofKRAS(G12C) and EGFR(L858R/T790M). These inhibitorsexhibited strong antiproliferative activities against cancer cells.Our findings provide valuable insights for designing dihaloacetamide-basedreversible covalent inhibitors.