Protein cereblon (CRBN) (CRBN)

Protein cereblon (CRBN) is a 442-amino acid protein that functions as the substrate recognition subunit of the CRL4^CRBN E3 ubiquitin ligase complex (UniProt Q96SW2). It is the primary molecular target for immunomodulatory imide drugs (IMiDs) and next-generation Cereblon E3 Ligase Modulators (CELMoDs) such as BMS-986458 (PubMed: 20223979). When these small molecules bind to the thalidomide-binding domain of CRBN, they induce a conformational change that allows the complex to recruit non-physiological neosubstrate proteins for ubiquitination and subsequent proteasomal degradation (PubMed: 24284190). The most prominent neosubstrates are the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), whose degradation leads to potent tumoricidal effects in B-cell malignancies like multiple myeloma. Additionally, CRBN-mediated degradation of these substrates enhances T-cell and natural killer (NK) cell activity, contributing to the drug's immunomodulatory profile. Beyond its role in oncology, CRBN is involved in physiological processes such as limb development and the regulation of large-conductance calcium-activated potassium channels in the brain. Mutations in the CRBN gene are associated with autosomal recessive intellectual disability, highlighting its importance in neural development (PubMed: 15543492). Therapeutic challenges include the risk of teratogenicity, which is a class-wide concern for CRBN-targeting agents, and the development of resistance through CRBN downregulation or mutation.

Other names

CereblonCRBNAD-06MRT14

Cereblon E3 ligase modulation (CELMoD) leading to the recruitment and proteasomal degradation of neosubstrate proteins such as IKZF1 and IKZF3.