2. Academic Validation
  3. Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells

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

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: kharasm@mskcc.org.
  • 5 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Broad Institute, Cambridge, MA, USA. Electronic address: cwoo@chemistry.harvard.edu.
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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