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- Title
KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma.
- Authors
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 Jr., Joseph J.; Schneekloth Jr, John S.; Chari, Raj; Kowalczyk, Joshua T.; Shenoy, Shilpa R.; Evans, Jason R.; Song, Young K.; Wang, Chaoyu; Wen, Xinyu; Chou, Hsien-Chao
- 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. There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.
- Subjects
HISTONE demethylases; RHABDOMYOSARCOMA
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-45902-y