Cereblon (CRBN)–Ikaros family zinc finger protein 3 (IKZF3) interface (CRBN–IKZF3 interface)

The Cereblon (CRBN)–Ikaros family zinc finger protein 3 (IKZF3) interface is a pharmacologically induced protein-protein interaction that serves as the primary therapeutic target for immunomodulatory imide drugs (IMiDs) and Cereblon E3 ligase modulators (CELMoDs). This interface is formed when a drug molecule binds to the thalidomide-binding domain of Cereblon, which is the substrate recognition component of the CRL4 E3 ubiquitin ligase complex (PMID: 25043012). The binding of the drug acts as a molecular glue, altering the surface of CRBN to create a high-affinity recruitment site for the transcription factor IKZF3, also known as Aiolos (PMID: 24292625). Once IKZF3 is recruited to the CRBN–drug complex, it undergoes polyubiquitination and is subsequently degraded by the 26S proteasome (PMID: 24292622). IKZF3 is a critical regulator of B-cell development and is essential for the survival of plasma cells; therefore, its degradation leads to cell cycle arrest and apoptosis in B-cell malignancies like multiple myeloma (UniProt: Q9UKL3). Furthermore, the degradation of IKZF3 in T-cells leads to increased production of interleukin-2, enhancing the immune system's ability to attack tumor cells. This target is central to the treatment of multiple myeloma and is being actively investigated for other hematologic cancers and autoimmune diseases such as systemic lupus erythematosus. Monitoring CRBN expression and IKZF3 degradation levels serves as a key strategy for predicting drug efficacy and understanding resistance mechanisms in clinical settings.

Other names

Cereblon–Aiolos interfaceCRBN–Aiolos interactionIMiD-induced CRBN–IKZF3 complexCereblon–Aiolos complex

Molecular glue-mediated degradation where a small molecule binds to Cereblon to induce the recruitment, ubiquitination, and proteasomal degradation of the neo-substrate IKZF3.