Ikaros family zinc finger protein 1 and 3 (IKZF1/3)

Ikaros family zinc finger protein 1 (IKZF1) and Ikaros family zinc finger protein 3 (IKZF3), commonly referred to as Ikaros and Aiolos, are transcription factors essential for the development and homeostasis of the hematopoietic system, particularly B and T cell lineages [1, 2]. These proteins function by binding to specific DNA sequences to regulate gene expression patterns necessary for lymphocyte maturation and the suppression of alternative cell fates [3]. In hematologic malignancies such as multiple myeloma, IKZF1 and IKZF3 are co-opted to maintain the expression of survival factors like IRF4 [4]. They are the definitive targets of immunomodulatory imide drugs (IMiDs), including lenalidomide and pomalidomide, which act as molecular glues to facilitate a de novo interaction between these transcription factors and the Cereblon (CRBN) E3 ubiquitin ligase complex [5, 6]. This interaction leads to the rapid ubiquitination and proteasomal degradation of IKZF1 and IKZF3, resulting in cytotoxic effects on malignant B cells and stimulatory effects on T cells through the derepression of interleukin-2 [7]. Beyond oncology, these factors are implicated in the pathogenesis of autoimmune diseases like systemic lupus erythematosus, making them high-value targets for next-generation degraders [8].

Other names

Ikaros (IKZF1)Aiolos (IKZF3)ZNFN1A1ZNFN1A3IK1IK3Ikaros family zinc finger 1Ikaros family zinc finger 3

Molecular glue-induced targeted protein degradation via the CRL4-CRBN E3 ubiquitin ligase complex