Ikaros family zinc finger protein 1 (IKZF1) via Cereblon (CRBN) E3 ubiquitin ligase complex (IKZF1/CRBN)

Ikaros family zinc finger protein 1 (IKZF1) is a critical transcription factor involved in the regulation of lymphocyte development and hematopoietic stem cell differentiation (UniProt Q13422). While not a traditional druggable target due to its lack of a small-molecule binding pocket, IKZF1 has become a focal point in oncology through the use of molecular glues that utilize the Cereblon (CRBN) E3 ubiquitin ligase complex (Ito et al., Science 2010). Immunomodulatory imide drugs (IMiDs), such as lenalidomide and pomalidomide, bind to the CRBN substrate receptor, altering its surface to facilitate the recruitment and subsequent degradation of IKZF1 (Lu et al., Science 2014). This degradation leads to the suppression of essential survival factors like IRF4 and MYC, particularly in B-cell malignancies such as multiple myeloma (Kronke et al., Science 2014). Beyond cancer, the IKZF1-CRBN axis is being investigated for its role in modulating immune responses in autoimmune conditions like systemic lupus erythematosus (Benjamin et al., J. Clin. Invest. 2022). The therapeutic application of this target is highly effective but carries significant safety considerations, including teratogenicity and hematologic toxicities like neutropenia (PubChem).

Other names

IkarosZNFN1A1LYF1IK1Cereblon-mediated IKZF1 degradation

Molecular glue-induced targeted protein degradation