Cereblon (CRBN) (CRBN)

Cereblon (CRBN) is a 442-amino acid protein that functions as the substrate recognition component of the CRL4^CRBN E3 ubiquitin ligase complex, which includes DDB1, CUL4A, and RBX1 (UniProt Q96SW2). In its physiological role, CRBN mediates the ubiquitination and subsequent proteasomal degradation of various endogenous proteins to regulate cellular metabolism and development. The target is clinically significant as the primary binding site for immunomodulatory imide drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide (PubMed: 20616233). Upon drug binding, CRBN undergoes a conformational change that enables it to act as a molecular glue, recruiting non-native neosubstrates like the transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos) (Science, 2014, 343(6168):301-305). The subsequent proteasomal degradation of these neosubstrates leads to the downregulation of essential survival factors like IRF4 and MYC, which is particularly effective in treating hematological malignancies such as multiple myeloma and del(5q) myelodysplastic syndrome (Blood, 2015, 125(18):2804-2814). Beyond oncology, CRBN-mediated degradation is being leveraged in the development of Proteolysis Targeting Chimeras (PROTACs) to target previously undruggable proteins. However, the use of CRBN-targeting drugs is associated with significant safety concerns, most notably severe teratogenicity and myelosuppression (Nature, 2010, 464(7287):441-444). Resistance to these therapies often arises through the loss of CRBN expression or mutations in the CRBN-binding pocket, highlighting its role as a critical biomarker for clinical response (Nature Communications, 2018, 9:2107).

Other names

CRBNCereblon E3 ubiquitin ligase complexCRL4-CRBNProtein cereblon

Molecular glue-induced recruitment and degradation of neosubstrates IKZF1 and IKZF3 via the CRL4^CRBN E3 ubiquitin ligase complex