Recent advances in the development of small-molecule drugs based on covalent reversible inhibitors.

Reversible covalent inhibitors (RCIs) are a class of small-molecule drugs that engage target proteins through covalent bonds. Unlike irreversible covalent inhibitors, RCIs can dissociate from their target. This reversibility, combined with high selectivity, arises from a binding mechanism that requires both the spatial conformation of the target protein and the reactivity of its residues. Serving as a bridge between traditional non-covalent inhibitors and irreversible covalent inhibitors, RCIs have attracted considerable attention in drug discovery, particularly for kinases, proteases, and other therapeutically relevant targets. In this review, we summarize recent advances in the development of electrophilic warheads designed for specific amino acid residues and the corresponding strategies for RCI design.