CRBN-PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications.

Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as a therapeutic target in cancer. CRBN regulates the degradation of various proteins in cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are a novel approach that uses the cell's degradation system to remove disease-causing proteins selectively. CRBN-dependent PROTACs work by tagging harmful proteins for destruction through the ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, including the potential to overcome drug resistance. Recent progress in developing CRBN-based PROTACs has shown promising preclinical results in both hematologic malignancies and solid tumors. Additionally, CRBN-based PROTACs have enhanced our understanding of CRBN's role in cancer, potentially serving as biomarkers for patient stratification and predicting therapeutic responses. In this review, we delineate the mechanisms of action for CRBN-dependent PROTACs (CRBN-PROTACs), summarize recent advances in preclinical and clinical applications, and provide our perspective on future development.