Last update 01 Nov 2024

FOXO1 x PAX3 x KDM1A

Last update 01 Nov 2024

Basic Info

Related Targets

FOXO1PAX3KDM1A

Drugs associated with FOXO1 x PAX3 x KDM1A

PFI-90

Target

FOXO1 x KDM1A x PAX3

Mechanism

FOXO1 gene inhibitors [+2]

Active Org.

National Cancer Institute

Originator Org.

National Cancer Institute

Active Indication

Rhabdomyosarcoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with FOXO1 x PAX3 x KDM1A

100 Translational Medicine associated with FOXO1 x PAX3 x KDM1A

0 Patents (Medical) associated with FOXO1 x PAX3 x KDM1A

Literatures (Medical) associated with FOXO1 x PAX3 x KDM1A

Nature CommunicationsQ1 · CROSS-FIELD

KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma

Q1 · CROSS-FIELD

ArticleOA

Author: Procter, Lauren ; Wei, Jun S ; Shern, Jack F ; O'Neill, Maura ; Evans, Jason R ; Peach, Megan L ; O'Keefe, Barry R ; Stanton, Benjamin Z ; Khan, Javed ; Barchi, Joseph J ; Esposito, Dominic ; Hawley, Robert G ; Woldemichael, Girma M ; Milewski, David ; Tarasova, Nadya I ; Wen, Xinyu ; Jones, Jane ; Wang, Chaoyu ; Pomella, Silvia ; Kim, Yong Yean ; Chou, Hsien-Chao ; Abdelmaksoud, Abdalla ; Gryder, Berkley E ; Jenkins, Lisa M ; 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.

Nature Communications

The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis

Article

Author: Clark, Ashleigh ; Norris, Murray D ; Low, Jason K K ; Mackay, Joel P ; Keating, Joanna ; Koster, Jan ; Milazzo, Giorgio ; Rouaen, Jourdin R C ; Wilkinson-White, Lorna ; Kusuma, Frances K ; Marshall, Glenn M ; Murray, Jayne E ; Sekyere, Eric O ; Perini, Giovanni ; Gao, Weiman ; De Rosa, Piergiuseppe ; Eden, Georgina ; Forgham, Helen ; Giorgi, Federico M ; Russell, Amanda J ; Jayatilleke, Nisitha ; Santulli, Martina ; Hilton, Douglas J ; Xue, Chengyuan ; Gifford, Andrew J ; Mayoh, Chelsea ; Valli, Emanuele ; Kile, Benjamin T ; Fleuren, Emmy D G ; Salehzadeh, Firoozeh ; Webber, Hannah ; Allan, Sophie ; de Weck, Antoine ; Haber, Michelle ; Fletcher, Jamie I ; Carter, Daniel R ; Gamble, Laura D ; Alfred, Stephanie

AbstractMYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.

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