A double-edged sword of neo-substrate degradation in PROTACs.

Immunomodulatory drugs (IMiDs), including thalidomide and its derivatives, serve as widely used E3 ligase ligand for cereblon (CRBN) recruitment in proteolysis targeting chimeras (PROTACs) development. CRBN-based PROTACs may independently induce neo-substrate degradation while mediating target protein degradation. The synergistic effects of IMiD-PROTACs present innovative therapeutic strategy for disease treatment. However, conversely, such off-target degradation potentially contributing to several toxic liabilities. This perspective systematically reviews current advances in harnessing synergistic effects and mitigating neo-substrates degradation in CRBN-based PROTACs research and development. Additionally, we comprehensively discuss medicinal chemistry strategies to eliminate off-target effects associated with neo-substrate degradation in CRBN-based PROTAC systems. This work provides guidance for optimizing CRBN-based PROTACs through rational modulation of neo-substrates degradation, enabling either elimination or preservation of these effects as therapeutically required.