Recent discoveries of CRBN-binding molecular glue degraders: Focus on protein kinases

Cereblon (CRBN)-based molecular glue degraders (MGDs) have emerged as one of the most rapidly evolving therapeutic modalities in targeted protein degradation. Upon binding of MGDs such as immunomodulatory drugs, CRBN undergoes an allosteric transition into a degradation-competent closed conformation, enabling the recruitment of structurally compatible neosubstrates for subsequent ubiquitination and proteasomal degradation. Recently, the repertoire of CRBN neosubstrates has rapidly expanded beyond the classical IMiD neosubstrates such as IKZF1/3 and CK1α. In particular, many therapeutically relevant protein kinases have been identified as CRBN neosubstrates including WEE1, NEK7, CDK2, CDK4, mTOR, LCK, ALK, TBK1, and IRAK1. Moreover, structural analyses of recently developed, potent and selective kinase MGDs have demonstrated that kinase recruitment extends far beyond the canonical β-hairpin G-loop degron. It encompasses diverse structural elements including α-helical G-loop degrons, αC helix glutamate, α-helical degron surfaces, and protein complex composite surfaces. These unique, target-specific engagement modes underpin the exceptional selectivity of these novel kinase degraders. Furthermore, because CRBN-based kinase MGDs deplete both the enzymatic and non-catalytic functions of target kinases, kinase MGDs can overcome resistance associated with conventional ATP-competitive kinase inhibitors and enhance therapeutic efficacy, particularly in combination therapies. This review provides a comprehensive overview of recent advances in CRBN-based kinase MGDs, highlighting compound optimization, structural basis of kinase recognition, mechanisms of action, and therapeutic potential.