The role of reversible and irreversible covalent chemistry in targeted protein degradation

Proteolysis-targeting chimeras (PROTACs) that degrade disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system have emerged as an exciting and transformative technology in both chemical biology and drug discovery. Currently, the majority of PROTACs use reversible non-covalent ligands for both the target protein of interest (POI) and E3 ligase. In this review, we explore the burgeoning role of reversible and irreversible covalent chemistry in targeted protein degradation. We highlight the key advantages of targeted covalent inhibitors, whether as the target POI or E3 ligase ligand, such as their ability to enhance the selectivity of PROTACs, enable access to more of the "undruggable" proteome and expand the repertoire of recruited E3 ligases.