Cereblon (CRBN) E3 ubiquitin ligase complex with Ikaros (IKZF1) and Aiolos (IKZF3) substrates (CRL4-CRBN-IKZF1/3)

The Cereblon (CRBN) E3 ubiquitin ligase complex, specifically the CRL4-CRBN assembly, is a critical therapeutic target in hematologic malignancies (Fischer et al., Nature, 2014). CRBN acts as the substrate recognition component of the Cullin-4-RING ligase complex. In the presence of immunomodulatory drugs (IMiDs) or Cereblon E3 ligase modulators (CELMoDs), CRBN undergoes a conformational change that allows it to recruit neomorphic substrates, most notably the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) (Kronke et al., Science, 2014). These transcription factors are essential for the survival of B-cell lineages and plasma cells. Their drug-induced ubiquitination and subsequent proteasomal degradation lead to the downregulation of downstream targets like IRF4 and MYC, resulting in cell cycle arrest and apoptosis in multiple myeloma cells (Chamberlain et al., Nat Struct Mol Biol, 2014). Beyond oncology, modulating this complex is being explored for autoimmune diseases like systemic lupus erythematosus due to its role in regulating T-cell and B-cell activity (Bristol Myers Squibb, 2023). The complex's ability to be redirected toward different substrates makes it a foundational model for molecular glue drug discovery.

Other names

CRBN-CRL4 complexCereblon-Ikaros/Aiolos axisCRL4CRBNCereblon-IKZF1-IKZF3 complex

Molecular glue degradation; drugs bind to the thalidomide-binding domain of Cereblon, altering its surface to facilitate the recruitment, ubiquitination, and proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3) (Kronke et al., Science, 2014).