Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells Journal Article

   


Authors: Park, S. M.; Miyamoto, D. K.; Han, G. Y. Q.; Chan, M.; Curnutt, N. M.; Tran, N. L.; Velleca, A.; Kim, J. H.; Schurer, A.; Chang, K.; Xu, W.; Kharas, M. G.; Woo, C. M.
Article Title: Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells
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. © 2023 Elsevier Inc.
Keywords: genetics; leukemia, myeloid, acute; mouse; animal; metabolism; animals; mice; transcription factor; transcription factors; hematopoiesis; ikaros transcription factor; acute myeloid leukemia; cereblon; humans; human; casein kinase ialpha; targeted protein degradation; ikzf2; casein kinase 1 alpha; ikzf2 protein, human
Journal Title: Cancer Cell
Volume: 41
Issue: 4
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2023-04-10
Start Page: 726
End Page: 739.e11
Language: English
DOI: 10.1016/j.ccell.2023.02.010
PUBMED: 36898380
PROVIDER: scopus
PMCID: PMC10466730
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85151255273&doi=10.1016%2fj.ccell.2023.02.010&partnerID=40&md5=25bd6c68d5dbceab438938df78058b24
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding author is MSK author Michael G. Kharas -- Source: Scopus
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MSK Authors
  1. Jun Hyun Kim
    13 Kim
  2. Michael Kharas
    100 Kharas
  3. Sun Mi Park
    23 Park
  4. Alexandra Schurer
    15 Schurer
  5. Anthony John Velleca
    7 Velleca
  6. Grace Yq Han
    7 Han
  7. Mandy Chan
    6 Chan
  8. Kathryn Chang
    8 Chang
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