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Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells. | LitMetric

AI Article Synopsis

  • Acute myeloid leukemia (AML) treatment is being explored through the development of new drugs that target epigenetic regulators, specifically IKZF2 and CK1α.
  • Two compounds, DEG-35 and DEG-77, were created to degrade these targets, with DEG-35 exhibiting strong effectiveness in blocking the growth of AML cells and promoting cell differentiation.
  • The research indicates that targeting both IKZF2 and CK1α improves treatment outcomes in AML models, showcasing a potential strategy for treating this type of leukemia and possibly other related illnesses.

Article Abstract

Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cells through CK1α-p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or a more soluble analog, DEG-77, delays leukemia progression in murine and human AML mouse models. Overall, we provide a strategy for multitargeted degradation of IKZF2 and CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466730PMC
http://dx.doi.org/10.1016/j.ccell.2023.02.010DOI Listing

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