Cell‐Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR‐ABL Kinase

Abstract Despite recent interests in developing lysine‐targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a develop cell‐active inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde‐based imine chemistries. validated strategy successfully (irreversible reversible) against BCR‐ABL kinase. Our lead compounds showed high levels selectivity biochemical assays, exhibited nanomolar potency endogenous ABL kinase cellular were active most drug‐resistant mutations. Among them, salicylaldehyde‐containing A5 first‐ever reversible inhibitor that possessed time‐dependent inhibition with prolonged residence time few off‐targets K562 cells. Bioinformatics further suggested generality our human kinome.