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KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma

Author

Listed:
  • Yong Yean Kim

    (Genetics Branch, NCI, NIH)

  • Berkley E. Gryder

    (Genetics Branch, NCI, NIH
    Case Western Reserve University)

  • Ranuka Sinniah

    (Genetics Branch, NCI, NIH)

  • Megan L. Peach

    (Basic Science Program, Frederick National Laboratory for Cancer Research (FNLCR))

  • Jack F. Shern

    (Pediatric Oncology Branch, NCI, NIH)

  • Abdalla Abdelmaksoud

    (Collaborative Bioinformatics Resource, NCI, NIH)

  • Silvia Pomella

    (Genetics Branch, NCI, NIH
    Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS)

  • Girma M. Woldemichael

    (Leidos Biomed Res Inc, FNLCR, Basic Sci Program
    Molecular Targets Program, NCI, NIH)

  • Benjamin Z. Stanton

    (Genetics Branch, NCI, NIH
    Nationwide Children’s Hospital, Center for Childhood Cancer Research
    The Ohio State University College of Medicine
    The Ohio State University College of Medicine)

  • David Milewski

    (Genetics Branch, NCI, NIH)

  • Joseph J. Barchi

    (Chemical Biology Laboratory, NCI, NIH)

  • John S. Schneekloth

    (Chemical Biology Laboratory, NCI, NIH)

  • Raj Chari

    (Genome Modification Core, Laboratory Animal Sciences Program, FNLCR)

  • Joshua T. Kowalczyk

    (Genetics Branch, NCI, NIH)

  • Shilpa R. Shenoy

    (Leidos Biomed Res Inc, FNLCR, Basic Sci Program
    Molecular Targets Program, NCI, NIH)

  • Jason R. Evans

    (Natural Products Branch, NCI, NIH)

  • Young K. Song

    (Genetics Branch, NCI, NIH)

  • Chaoyu Wang

    (Genetics Branch, NCI, NIH)

  • Xinyu Wen

    (Genetics Branch, NCI, NIH)

  • Hsien-Chao Chou

    (Genetics Branch, NCI, NIH)

  • Vineela Gangalapudi

    (Genetics Branch, NCI, NIH)

  • Dominic Esposito

    (Protein Expression Laboratory, FNLCR, NIH)

  • Jane Jones

    (Protein Expression Laboratory, FNLCR, NIH)

  • Lauren Procter

    (Protein Expression Laboratory, FNLCR, NIH)

  • Maura O’Neill

    (Protein Characterization Laboratory, FNLCR, NIH)

  • Lisa M. Jenkins

    (Laboratory of Cell Biology, NCI, NIH)

  • Nadya I. Tarasova

    (Cancer Innovation Laboratory, NCI, NIH)

  • Jun S. Wei

    (Genetics Branch, NCI, NIH)

  • James B. McMahon

    (Molecular Targets Program, NCI, NIH)

  • Barry R. O’Keefe

    (Molecular Targets Program, NCI, NIH
    Natural Products Branch, NCI, NIH)

  • Robert G. Hawley

    (Genetics Branch, NCI, NIH
    George Washington University)

  • Javed Khan

    (Genetics Branch, NCI, NIH)

Abstract

Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.

Suggested Citation

  • Yong Yean Kim & Berkley E. Gryder & Ranuka Sinniah & Megan L. Peach & Jack F. Shern & Abdalla Abdelmaksoud & Silvia Pomella & Girma M. Woldemichael & Benjamin Z. Stanton & David Milewski & Joseph J. B, 2024. "KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45902-y
    DOI: 10.1038/s41467-024-45902-y
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    References listed on IDEAS

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