Cereblon (CRBN) E3 ubiquitin ligase complex with recruited neosubstrates Ikaros family zinc finger protein 1 (IKZF1) and Ikaros family zinc finger protein 3 (IKZF3) (CRBN-IKZF1/3)

Cereblon (CRBN) is a protein that functions as the substrate receptor for the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex (UniProt Q96SW2). While its endogenous roles include regulating ion channels and metabolic pathways, it is the primary target for immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide (Ito et al., Science 2010, PMID: 20223979). These drugs act as molecular glues, altering the substrate specificity of CRBN to recruit non-native proteins, termed neosubstrates, for ubiquitination and proteasomal degradation. The most clinically significant neosubstrates are the zinc-finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for B-cell development and survival (Lu et al., Science 2014, PMID: 24292625). In multiple myeloma, the drug-induced degradation of Ikaros and Aiolos leads to the suppression of downstream targets like IRF4, resulting in potent anti-proliferative and pro-apoptotic effects (Krönke et al., Science 2014, PMID: 24292624). Beyond oncology, this axis is being targeted for autoimmune conditions like systemic lupus erythematosus due to its role in modulating B-cell and T-cell activity. Safety considerations remain paramount, as CRBN-mediated degradation of other substrates like SALL4 is linked to the teratogenic effects of thalidomide (Donovan et al., eLife 2018, PMID: 30067223).

Other names

CRBN-CRL4 complexCereblon-Ikaros-Aiolos axisIMiD-CRBN complexCereblon E3 ligase modulator (CELMoD) target

Molecular glue-induced recruitment of neosubstrates (IKZF1 and IKZF3) to the CRL4-CRBN E3 ubiquitin ligase complex, leading to their polyubiquitination and subsequent proteasomal degradation (Science 2014, PMID: 24292625).