Covalent chemistry in targeted protein degradation

Targeted protein degradation (TPD) has revolutionized drug discovery by enabling the selective removal of specific proteins within and outside cells through the cell's natural degradation pathways. While various TPD modalities have demonstrated immense promise, the integration of covalent chemistry is rapidly emerging as a crucial approach to enhance target engagement, improve selectivity, and overcome limitations associated with non-covalent interactions. This review provides a comprehensive overview of the current landscape of covalent TPD and systematically explores how covalent chemistry advances the field of TPD. We first detail the diverse covalent modification strategies, reactive amino acid residues, and electrophilic warheads employed in the design of covalent ligands. Next, we discuss methodologies for covalent ligand discovery, including ligand-first and electrophile-first approaches. Finally, we highlight specific examples of covalent degraders across different TPD modalities, emphasizing their mechanisms of action and therapeutic potential. By integrating current knowledge and future directions, this review aims to provide insights for the rational design of next-generation covalent degraders and underscore their implications for the future of drug discovery.