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, Javed Khan
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...
February 24, 2024: Nature Communications