GSE219199 KDM3B inhibitors disrupt PAX3-FOXO1 oncogenic activity in fusion positive rhabdomyosarcoma.

Contributors : Yong Y Kim ; Javed Khan ; Xinyu Wen ; Hsien-Chao ChouSeries Type : Expression profiling by high throughput sequencing ; Genome binding/occupancy profiling by high throughput sequencing ; OtherOrganism : Homo sapiensFusion-positive alveolar rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. We screened 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, PFI-63. RNA-seq, ATAC-seq, and docking analyses implicated histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirmed the inhibition of multiple KDMs with highest selectivity for KDM3B. Structural similarity search of PFI-63 identified PFI-90 with improved solubility and potency. Biophysical binding of PFI-90 to KDM3B was demonstrated using NMR and SPR. PFI-90 suppressed the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopied PFI-90 effects. Thus, we report novel KDM inhibitors with highest specificity for KDM3B. Its potent suppression of PAX3-FOXO1 activity can be exploited as a new therapeutic approach for FP-RMS and other transcriptionally driven cancers.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing Other Homo sapiens Source Type: research