Cereblon (CRBN)–Ikaros family zinc finger protein 1 (IKZF1) interface (CRBN–IKZF1 interface)

The Cereblon (CRBN)–Ikaros family zinc finger protein 1 (IKZF1) interface is a pharmacologically induced protein-protein interaction that serves as a primary therapeutic target in hematologic malignancies. Cereblon (CRBN) functions as the substrate recognition component of the CRL4^CRBN E3 ubiquitin ligase complex (UniProt Q96SW2). Ikaros (IKZF1) is a lymphoid-restricted transcription factor essential for B-cell development and hematopoietic stem cell differentiation (UniProt Q13422). Under normal physiological conditions, CRBN does not interact with IKZF1; however, the administration of immunomodulatory imide drugs (IMiDs) such as lenalidomide or pomalidomide creates a molecular glue effect. These drugs bind to the thalidomide-binding domain of CRBN, altering its surface properties to facilitate the recruitment of IKZF1 as a "neo-substrate" (Fischer et al., Nature 2014; Krönke et al., Science 2014). This recruitment leads to the polyubiquitination of IKZF1 and its subsequent degradation by the 26S proteasome. In multiple myeloma, the depletion of IKZF1 results in the downregulation of downstream targets like IRF4 and MYC, which are critical for plasma cell survival, thereby inducing cell death (Gandhi et al., Blood 2014). Beyond oncology, the CRBN–IKZF1 axis is being explored for autoimmune conditions like systemic lupus erythematosus, where IKZF1 degradation can modulate immune cell activity.

Other names

CRBN-IKZF1 complexCereblon-Ikaros interfaceIMiD-induced neo-substrate interfaceCRL4-CRBN-IKZF1 complex

Molecular glue-mediated recruitment of the neo-substrate IKZF1 to the CRL4-CRBN E3 ubiquitin ligase complex, resulting in its polyubiquitination and subsequent proteasomal degradation.