Molecular glues: Recent advances in cereblon substrate identification and mechanistic insights

This highlight summarizes the recent advances in cereblon (CRBN) substrate discovery and mechanisms of action within the field of molecular glues. It emphasizes that molecular glue technology has transitioned from the stage of monofunctional targeted protein degradation to that of rational design and multidimensional regulation. Key recent breakthroughs include: (1) overcoming the limitations of canonical CRBN recognition motifs, identifying extensive novel substrates and unconventional recognition modes independent of fixed specific secondary structures; (2) reconceptualizing G protein-coupled receptor (GPCR) signal transduction theory by demonstrating that molecular glues can stabilize GPCR megacomplexes to achieve sustained signal modulation, providing a novel strategy to overcome the challenge of traditional drug tolerance; (3) pioneering the concept of orthosteric molecular glue inhibitors, which expands the mechanistic modalities of molecular glues. Furthermore, this highlight delineates the therapeutic potential and mechanistic basis of molecular glues in antiviral therapies against HIV and the mpox virus, corroborating their core essence of inducing or stabilizing protein-protein interactions. Finally, it summarizes current challenges facing the field, including target discovery, rational design, and druggability optimization, aiming to provide a theoretical reference for innovative research and development of molecular glues and their applications in chronic diseases and antiviral therapies.