Progress of structurally diverse cereblon (CRBN) ligands and their application in PROTAC degraders

Protein degradation-targeting chimeras (PROTACs) degrade target proteins by hijacking the ubiquitin-proteasome pathway, and their unique mechanism of action has attracted great attention from the scientific community over the past decade. In recent years, the field has achieved significant advancements, mainly due to the advent of various E3 ligase ligands and their prevalent application in the design of PROTACs. To date, more than ten E3 ligases have been exploited for the development of PROTACs. Notably, recruiting cereblon (CRBN) represents one of the most widely reported strategies in PROTAC design, attributed to the widespread expression across various tissues of CRBN and the favorable drug-like characteristics and synthetic accessibility of classical CRBN ligands, immunomodulatory imide drugs (IMiDs). Nevertheless, IMiDs face significant challenges, including inducing neo-substrate degradation, inherent racemization, and readily undergoing hydrolysis. In recent years, numerous structurally diverse CRBN ligands with enhanced selectivity and stability have been synthesized for the development of PROTACs. This review provides a systematic overview of the development of CRBN ligands with distinct structural scaffolds reported in peer-reviewed literature, focusing on activity optimization processes, structure-activity relationship investigations, and their practical applications in PROTACs design. Additionally, we further summarize conditionally activated CRBN-based PROTACs with reduced off-target toxicity. The aim is to offer both practical insights and innovative perspectives for future investigations in this fast-evolving field.