Ikaros family zinc finger protein 1 (IKZF1) and Ikaros family zinc finger protein 3 (IKZF3) in complex with Cereblon (CRBN) (IKZF1/IKZF3-CRBN)

The complex consisting of Ikaros family zinc finger protein 1 (IKZF1) and Ikaros family zinc finger protein 3 (IKZF3) in complex with Cereblon (CRBN) is a primary therapeutic target in hematologic malignancies (UniProt Q96SW2, Q13422). IKZF1 (Ikaros) and IKZF3 (Aiolos) are essential transcription factors for B-cell development and the survival of malignant plasma cells (PubMed: 24433972). In the presence of immunomodulatory imide drugs (IMiDs) such as lenalidomide or pomalidomide, CRBN acts as a substrate receptor that recruits these transcription factors as neo-substrates. This recruitment leads to the polyubiquitination of IKZF1 and IKZF3 by the CRL4-CRBN E3 ligase complex, followed by their degradation by the 26S proteasome (Science, 2014, 343(6168):301-305). The loss of these transcription factors results in the downregulation of downstream targets like IRF4 and MYC, leading to cell cycle arrest and apoptosis in multiple myeloma cells (Nature Reviews Cancer, 2018). This molecular glue mechanism is also being leveraged for the development of Cereblon E3 ligase modulators (CELMoDs) to treat autoimmune diseases like systemic lupus erythematosus (Clinical Cancer Research, 2023).

Other names

Ikaros and Aiolos in complex with CereblonCRL4-CRBN-IKZF1/3 complexCereblon-Ikaros-Aiolos complexIMiD-CRBN-IKZF1/3 complex

Molecular glue-induced targeted protein degradation via the CRL4-CRBN E3 ubiquitin ligase complex (Science, 2014, 343(6168):301-305).