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

Cereblon (CRBN) is the substrate recognition component of the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex and serves as the primary molecular target for immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide [1, 6]. In the presence of these drugs, CRBN acts as a molecular glue, undergoing a conformational change that enables the recruitment of non-native substrates, or neosubstrates, specifically the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) [4, 5]. These transcription factors are essential for the survival of B-cell malignancies, and their recruitment to the CRBN complex leads to their polyubiquitination and subsequent degradation by the 26S proteasome [2, 3, 5]. In multiple myeloma, the loss of Ikaros and Aiolos results in the downregulation of downstream targets such as IRF4 and MYC, triggering cell cycle arrest and apoptosis [4, 5]. Beyond its direct tumoricidal effects, the degradation of Aiolos in T-cells enhances interleukin-2 (IL-2) production, thereby stimulating an anti-tumor immune response [6]. This target complex is a cornerstone of modern hematologic oncology and is currently being investigated for applications in autoimmune diseases like systemic lupus erythematosus.

Other names

CRBN-CRL4 complexIkaros family zinc finger protein 1Ikaros family zinc finger protein 3Cereblon-neosubstrate complexIMiD-target complex

Molecular glue-mediated recruitment of neosubstrates (IKZF1 and IKZF3) to the CRL4-CRBN E3 ubiquitin ligase complex, leading to their polyubiquitination and subsequent proteasomal degradation.