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

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. Barchi, John S. Schneekloth, Raj Chari, Joshua T. Kowalczyk, Shilpa R. Shenoy, Jason R. Evans, Young K. Song, Chaoyu Wang, Xinyu Wen, Hsien-Chao Chou, Vineela Gangalapudi, Dominic Esposito, Jane Jones, Lauren Procter, Maura O’Neill, Lisa M. Jenkins, Nadya I. Tarasova, Jun S. Wei, James B. McMahon, Barry R. O’Keefe, Robert G. Hawley and Javed Khan ()
Additional contact information
Yong Yean Kim: Genetics Branch, NCI, NIH
Berkley E. Gryder: Genetics Branch, NCI, NIH
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
Girma M. Woldemichael: Leidos Biomed Res Inc, FNLCR, Basic Sci Program
Benjamin Z. Stanton: Genetics Branch, NCI, NIH
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
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
Robert G. Hawley: Genetics Branch, NCI, NIH
Javed Khan: Genetics Branch, NCI, NIH

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45902-y

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