Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells

Cancer Cell. 2023 Apr 10;41(4):726-739.e11. doi: 10.1016/j.ccell.2023.02.010. Epub 2023 Mar 9.

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.

Keywords: IKZF2; acute myeloid leukemia; casein kinase 1 alpha; cereblon; targeted protein degradation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Casein Kinase Ialpha* / genetics
  • Casein Kinase Ialpha* / metabolism
  • Hematopoiesis
  • Humans
  • Ikaros Transcription Factor / genetics
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Mice
  • Transcription Factors

Substances

  • Casein Kinase Ialpha
  • Ikaros Transcription Factor
  • IKZF2 protein, human
  • Transcription Factors