1区 · 综合性期刊
ArticleOA
作者: Procter, Lauren ; O'Neill, Maura ; Wei, Jun S ; Shern, Jack F ; Evans, Jason R ; Peach, Megan L ; O'Keefe, Barry R ; Khan, Javed ; Stanton, Benjamin Z ; Barchi, Joseph J ; Esposito, Dominic ; Woldemichael, Girma M ; Milewski, David ; Tarasova, Nadya I ; Wen, Xinyu ; Hawley, Robert G ; Jones, Jane ; Wang, Chaoyu ; Pomella, Silvia ; Kim, Yong Yean ; Chou, Hsien-Chao ; Abdelmaksoud, Abdalla ; Jenkins, Lisa M ; Gryder, Berkley E ; Song, Young K ; Chari, Raj ; Schneekloth, John S ; Gangalapudi, Vineela ; Shenoy, Shilpa R ; Sinniah, Ranuka ; McMahon, James B ; Kowalczyk, Joshua T
AbstractFusion-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.
