Cereblon (CRBN) recruiting Ikaros (IKZF1) and Aiolos (IKZF3) (CRBN-IKZF1/3)

The Cereblon (CRBN) complex recruiting Ikaros (IKZF1) and Aiolos (IKZF3) represents a critical therapeutic axis in hematologic oncology and immunology. CRBN functions as the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex, while IKZF1 and IKZF3 are zinc-finger transcription factors essential for B-cell development and the survival of plasma cells. In the presence of immunomodulatory imide drugs (IMiDs) or Cereblon E3 ligase modulators (CELMoDs), CRBN undergoes a conformational change that allows it to bind and ubiquitinate IKZF1 and IKZF3, leading to their rapid degradation by the 26S proteasome (Kronke et al., 2014, Nature; Lu et al., 2014, Science). This degradation results in the downregulation of downstream oncogenic drivers like IRF4 and MYC, inducing cell cycle arrest and apoptosis in multiple myeloma cells. Beyond direct tumor cytotoxicity, the degradation of these transcription factors in T-cells enhances interleukin-2 (IL-2) production, stimulating an anti-tumor immune response (Gandhi et al., 2014, Blood). This target is the primary mechanism for established therapies like Lenalidomide and is being further exploited by next-generation CELMoDs like Mezigdomide to overcome drug resistance in relapsed/refractory settings.

Other names

CRBN-Ikaros-Aiolos axisCereblon-mediated IKZF1/3 degradationIMiD target complexCRL4-CRBN-IKZF1/3Cereblon E3 ligase modulators (CELMoDs) target

Molecular glue degradation: The drug binds to the thalidomide-binding domain of Cereblon (CRBN), altering its surface to enable the recruitment and subsequent ubiquitination of the 'neo-substrates' Ikaros (IKZF1) and Aiolos (IKZF3) by the CRL4-CRBN E3 ligase complex, leading to their proteasomal degradation.