Cereblon (CRBN) E3 ubiquitin ligase complex with Ikaros (IKZF1) and Aiolos (IKZF3) neosubstrates (CRBN-IKZF1/3)

The Cereblon (CRBN) E3 ubiquitin ligase complex, when associated with the neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3), serves as the primary target for immunomodulatory imide drugs (IMiDs). CRBN functions as the substrate receptor for the CRL4-CRBN E3 ligase complex, which typically targets specific proteins for degradation to maintain cellular homeostasis (UniProt: Q96SW2). In the presence of drugs like lenalidomide or pomalidomide, CRBN undergoes a conformational change that enables it to recruit IKZF1 and IKZF3, transcription factors critical for B-cell development and lymphoid malignancy survival (PubMed: 24291798, 24291799). This recruitment leads to the polyubiquitination and subsequent proteasomal degradation of these neosubstrates. The depletion of Ikaros and Aiolos results in the downregulation of IRF4, leading to cell cycle arrest and apoptosis in multiple myeloma cells (PubMed: 24291803). This mechanism represents a paradigm for molecular glue degraders, where a small molecule redirects the activity of an E3 ligase toward non-native targets to achieve a therapeutic effect. Beyond oncology, the CRBN-IKZF1/3 axis is being investigated for its role in modulating immune responses in autoimmune conditions like systemic lupus erythematosus (PubMed: 30104371). Therapeutic challenges include the risk of teratogenicity, a historical concern with thalidomide, and the development of resistance through CRBN mutations or downregulation (PubMed: 25171465).

Other names

CRL4-CRBN complexCereblon-Ikaros-Aiolos axisCRBN-IKZF1-IKZF3 complex

Molecular glue-induced neosubstrate recruitment and proteasomal degradation