Covalent Recruitment of E3 Ligases: A New Path for Rational Design of Protein Degraders

ABSTRACT The covalent recruitment of E3 ubiquitin ligases is a rapidly advancing strategy in targeted protein degradation (TPD). While traditional non‐covalent PROTACs and molecular glues operate through transient binding equilibria that can limit catalytic efficiency, covalent degraders form irreversible bonds with E3 ligases, thereby stabilizing ternary complexes, enhancing degradation kinetics, and enabling a “pre‐assembly” mechanism in which the degrader remains bound to the E3 ligase after each degradation event to facilitate multi‐turnover catalysis. Recent advances in chemoproteomic platforms have enabled the systematic identification of ligandable amino acid residues across the E3 ligase landscape, transforming degrader discovery from serendipitous observation to rational structure‐guided design. This technological revolution has dramatically expanded the repertoire of recruitable E3 ligases beyond traditional candidates such as CRBN and VHL, thereby overcoming resistance mechanisms and enabling access to historically undruggable targets. This review systematically outlines the design principles of covalent E3‐targeting PROTACs and contrasts them with covalent E3‐targeting molecular glues. The latter achieve potent degradation through either template‐assisted covalent modification or the incorporation of transplantable electrophilic handles. We summarize representative covalent E3‐recruiting degraders, focusing on their design principles, mechanistic insights, and therapeutic potential. We further discuss key challenges and future directions, particularly the imperative to broaden E3 ligase coverage and diversify warhead chemistry, aiming to provide valuable insights for the development of covalent protein degraders.