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.
Sun-Mi Park  1 ,  David K Miyamoto  2 ,  Grace Y Q Han  1 ,  Mandy Chan  1 ,  Nicole M Curnutt  2 ,  Nathan L Tran  2 ,  Anthony Velleca  1 ,  Jun Hyun Kim  3 ,  Alexandra Schurer  1 ,  Kathryn Chang  1 ,  Wenqing Xu  2 ,  Michael G Kharas  4 ,  Christina M Woo  5
Affiliations
  • 1. Molecular Pharmacology Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 3. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4. Molecular Pharmacology Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].
  • 5. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Broad Institute, Cambridge, MA, USA. Electronic address: [email protected].
PMID: 36898380 DOI: 10.1016/j.ccell.2023.02.010
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.
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