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| Status |
Public on Dec 31, 2023 |
| Title |
KDM3B inhibitors disrupt PAX3-FOXO1 oncogenic activity in fusion positive rhabdomyosarcoma. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Other
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| Summary |
Fusion-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.
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| Overall design |
RNA-seq, ChIP-seq, ATAC-seq, Hi-C, scRNA-seq. No replicates. Drug treatment versus control analysis.
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| Contributor(s) |
Kim YY, Khan J, Wen X, Chou H |
| Citation(s) |
38402212 |
| Submission date |
Dec 01, 2022 |
| Last update date |
Mar 11, 2024 |
| Contact name |
Javed Khan |
| E-mail(s) |
khanjav@mail.nih.gov
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| Phone |
2407606135
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| Organization name |
NCI, NIH
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| Department |
Genetics Branch
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| Lab |
Javed Khan
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| Street address |
37 Convent Dr.
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL30173 |
NextSeq 2000 (Homo sapiens) |
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| Samples (79)
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| Relations |
| BioProject |
PRJNA907384 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE219199_RAW.tar |
1.8 Gb |
(http)(custom) |
TAR (of BED, HIC, MTX, TSV, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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