Cereblon

Cereblon (CRBN) is a protein encoded by the CRBN gene in humans. It serves as a substrate receptor component of the CRL4 E3 ubiquitin ligase complex, linking DDB1 to CUL4A/B, and directing ubiquitination and proteasomal degradation of selected target proteins.

In normal physiology, CRBN participates in various cellular processes through recognition of specific substrates; several IMiD-susceptible substrates have been identified, notably transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos) in lymphoid cells; others include SALL4. Substrate degradation influences lymphoid development, hematopoiesis, and cancer cell proliferation.

Cereblon is the primary molecular target of the immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide. Binding of IMiDs to CRBN reconfigures the CRL4-CRBN ubiquitin ligase to promote degradation of IKZF1/3, contributing to anti-tumor effects in multiple myeloma and other cancers. Thalidomide's teratogenic effects are also linked to CRBN-dependent degradation of developmental transcription factors.

Since its identification as the thalidomide-binding protein, CRBN has been a focus in drug development and cancer biology; CRBN remains under investigation for its full range of substrates and biological roles.