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

Authors

Yong Yean Kim, Genetics Branch, NCI, NIH, Bethesda, MD, USA. yong.kim@nih.gov.
Berkley E. Gryder, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Ranuka Sinniah, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Megan L. Peach, Basic Science Program, Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD, USA.
Jack F. Shern, Pediatric Oncology Branch, NCI, NIH, Bethesda, MD, USA.
Abdalla Abdelmaksoud, Collaborative Bioinformatics Resource, NCI, NIH, Bethesda, MD, USA.
Silvia Pomella, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Girma M. Woldemichael, Leidos Biomed Res Inc, FNLCR, Basic Sci Program, Frederick, MD, USA.
Benjamin Z. Stanton, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
David Milewski, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Joseph J. Barchi, Chemical Biology Laboratory, NCI, NIH, Frederick, MD, USA.
John S. Schneekloth, Chemical Biology Laboratory, NCI, NIH, Frederick, MD, USA.
Raj Chari, Genome Modification Core, Laboratory Animal Sciences Program, FNLCR, Frederick, MD, USA.
Joshua T. Kowalczyk, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Shilpa R. Shenoy, Leidos Biomed Res Inc, FNLCR, Basic Sci Program, Frederick, MD, USA.
Jason R. Evans, Natural Products Branch, NCI, NIH, Frederick, MD, USA.
Young K. Song, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Chaoyu Wang, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Xinyu Wen, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Hsien-Chao Chou, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Vineela Gangalapudi, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Dominic Esposito, Protein Expression Laboratory, FNLCR, NIH, Frederick, MD, USA.
Jane Jones, Protein Expression Laboratory, FNLCR, NIH, Frederick, MD, USA.
Lauren Procter, Protein Expression Laboratory, FNLCR, NIH, Frederick, MD, USA.
Maura O'Neill, Protein Characterization Laboratory, FNLCR, NIH, Frederick, MD, USA.
Lisa M. Jenkins, Laboratory of Cell Biology, NCI, NIH, Bethesda, MD, USA.
Nadya I. Tarasova, Cancer Innovation Laboratory, NCI, NIH, Bethesda, MD, USA.
Jun S. Wei, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
James B. McMahon, Molecular Targets Program, NCI, NIH, Frederick, MD, USA.
Barry R. O'Keefe, Molecular Targets Program, NCI, NIH, Frederick, MD, USA.
Robert G. Hawley, Genetics Branch, NCI, NIH, Bethesda, MD, USA.
Javed Khan, Genetics Branch, NCI, NIH, Bethesda, MD, USA. khanjav@mail.nih.gov.

Document Type

Journal Article

Publication Date

2-24-2024

Journal

Nature communications

Volume

15

Issue

1

DOI

10.1038/s41467-024-45902-y

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.

APA Citation

Kim, Yong Yean; Gryder, Berkley E.; Sinniah, Ranuka; Peach, Megan L.; Shern, Jack F.; Abdelmaksoud, Abdalla; Pomella, Silvia; Woldemichael, Girma M.; Stanton, Benjamin Z.; Milewski, David; Barchi, Joseph J.; Schneekloth, John S.; Chari, Raj; Kowalczyk, Joshua T.; Shenoy, Shilpa R.; Evans, Jason R.; Song, Young K.; Wang, Chaoyu; Wen, Xinyu; Chou, Hsien-Chao; Gangalapudi, Vineela; Esposito, Dominic; Jones, Jane; Procter, Lauren; O'Neill, Maura; Jenkins, Lisa M.; Tarasova, Nadya I.; Wei, Jun S.; McMahon, James B.; O'Keefe, Barry R.; Hawley, Robert G.; and Khan, Javed, "KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma" (2024). GW Authored Works. Paper 4313.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4313

Department

Anatomy and Regenerative Biology