Ikaros family zinc finger protein 1 and 3 via Cereblon E3 ubiquitin ligase complex (IKZF1/IKZF3-CRBN)

The IKZF1/IKZF3-CRBN axis is a critical therapeutic target primarily utilized in the treatment of hematologic malignancies and autoimmune disorders. IKZF1 (Ikaros) and IKZF3 (Aiolos) are zinc-finger transcription factors that play pivotal roles in the development and differentiation of B and T lymphoid lineages (UniProt Q13422, Q9UKT9). Therapeutic agents known as immunomodulatory imide drugs (IMiDs) and Cereblon E3 ligase modulators (CELMoDs) act as molecular glues, facilitating a de novo interaction between these transcription factors and Cereblon (CRBN), the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex (PubMed: 24284321). This interaction leads to the polyubiquitination and subsequent proteasomal degradation of IKZF1 and IKZF3. In multiple myeloma, the degradation of these proteins results in the downregulation of essential survival factors such as IRF4 and MYC, leading to cell cycle arrest and apoptosis (PubMed: 24284321, 24284322). Furthermore, the degradation of IKZF1/3 in T-cells enhances the production of interleukin-2 (IL-2), thereby stimulating an anti-tumor immune response. This dual mechanism of action—direct tumoricidal activity and immunomodulation—underpins the clinical efficacy of drugs like lenalidomide and pomalidomide, as well as next-generation degraders currently in clinical development (ClinicalTrials.gov).

Other names

IkarosAiolosCereblonIKZF1IKZF3CRBNCRL4-CRBN complex

Molecular glue-induced targeted protein degradation; recruitment of IKZF1 and IKZF3 to the CRBN-CRL4 E3 ligase complex for ubiquitination and proteasomal degradation.