Covalent lysine targeting is coming of age

Covalent lysine targeting is an active frontier in drug discovery and chemical biology as the field extends beyond covalent binding to cysteines. Targeting abundant and functionally diverse lysine residues presents unique opportunities for developing chemical strategies of protein modulation, with the potential to address previously unexplored areas of the proteome. In this review, we highlight recent key advancements in the field, emphasizing electrophilic chemistries, as well as various discovery methods for novel ligands. We review strategies for mapping lysine ‘ligandability’ and covalent lysine-targeting probe discovery. While the majority of reported covalent lysine binders are still designed in a ‘ligand-first’ approach, examples of ‘electrophile-first’ probes are now being reported. From a kinetic perspective, advanced lysine-covalent inhibitors are now approaching second-order reaction rates of Food and Drug Administration (FDA)-approved cysteine-targeting covalent drugs, underscoring the potential of lysine-targeting as a strategy for drug development.