Evolving CRBN ligands enhance the drug-like properties of protein degraders

Proteolysis-targeting chimaeras (PROTACs) enable event-driven degradation of disease-relevant proteins by hijacking the ubiquitin-proteasome system (UPS). Cereblon (CRBN) is the most widely exploited recruiter due to its well-characterised binding pocket and strong clinical precedent from immunomodulatory imide drugs (IMiDs). However, early CRBN ligands have suboptimal pharmacokinetics, off-target neosubstrate degradation, immunomodulatory liabilities, and resistance mechanisms, which restrict the drug-like properties of CRBN-based degraders. This review systematically summarises CRBN ligand evolution and how chemical innovations improved PROTAC drug-likeness. We discuss classical IMiD-based ligands and their clinical translation, followed by next-generation recruiters, including non-IMiD scaffolds, conformationally constrained tricyclic and spirocyclic ligands, cyclic imides, covalent ligands, and stimuli-responsive designs. We highlight expanding application of novel CRBN ligands in molecular glue degrader development. Finally, key challenges and future directions for achieving selective, durable, and clinically viable CRBN-mediated protein degradation are discussed.