Ikaros family zinc finger protein 1, Ikaros family zinc finger protein 3, and Casein kinase 1 alpha (IKZF1, IKZF3, CSNK1A1)

IKZF1 (Ikaros family zinc finger protein 1), IKZF3 (Ikaros family zinc finger protein 3), and CK1α (Casein kinase 1 alpha) are a group of proteins that serve as neomorphic substrates for the Cereblon (CRBN) E3 ubiquitin ligase complex [2, 4, 13]. These proteins are not naturally targeted by CRBN but are recruited to the ligase in the presence of immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, which act as molecular glues [4, 19]. IKZF1 and IKZF3 are transcription factors essential for the survival of multiple myeloma cells; their degradation leads to the downregulation of the IRF4-MYC transcriptional axis, resulting in cell death and enhanced T-cell activity [2, 10, 13]. CK1α is a serine/threonine kinase whose degradation is specifically induced by lenalidomide, providing a therapeutic window in del(5q) myelodysplastic syndrome (MDS) [4, 13]. In this disease setting, malignant cells are haploinsufficient for the CSNK1A1 gene, making them uniquely sensitive to further reduction of CK1α levels, which triggers p53-mediated apoptosis [14, 19]. The discovery of this mechanism has revolutionized the treatment of hematologic malignancies and established a paradigm for the development of targeted protein degradation (TPD) therapies [16, 18].

Other names

IkarosAiolosCK1αCasein kinase I isoform alphaZNFN1A1ZNFN1A3CSNK1A1LYF1

Targeted protein degradation via molecular glue-mediated recruitment to the CRL4-CRBN E3 ubiquitin ligase complex, leading to polyubiquitination and proteasomal degradation.