Differential effects, on oncogenic pathway signalling, by derivatives of the HNF4 α inhibitor BI6015

British Journal of Cancer
Jin-Hee KimJin-Hyun Jeong

Abstract

Gastric cancer (GC) is a highly heterogeneous disease with few "targeted" therapeutic options. Previously, we demonstrated involvement of the transcription factor HNF4α in human GC tumours, and the developmental signal mediator, WNT5A, as a prognostic GC biomarker. One previously developed HNF4α antagonist, BI6015, while not advancing beyond preclinical stages, remains useful for studying GC. Here, we characterised the antineoplastic signalling activity of derivatives of BI6015, including transfer of the nitro group from the para position, relative to a methyl group on its benzene ring, to the ortho- and meta positions. We assessed binding efficacy, through surface plasmon resonance and docking studies, while biologic activity was assessed by antimitogenic efficacy against a panel of GC cell lines, and dysregulated transcriptomes, followed by pathway and subpathway analysis. The para derivative of BI6105 was found substantially more growth inhibitory, and effective, in downregulating numerous oncogenic signal pathways, including the embryonic cascade WNT. The ortho and meta derivatives, however, failed to downregulate WNT or other embryonic signalling pathways, unable to suppress GC growth. Straightforward strategies, employing...Continue Reading

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Citations

Feb 6, 2020·The Pharmacogenomics Journal·Jin-Hee KimYon Hui Kim
Jun 4, 2019·Frontiers in Genetics·Seungyoon NamDae Ho Lee
Apr 26, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Shengjie XuNing Zhang
Mar 8, 2020·Cellular and Molecular Gastroenterology and Hepatology·Paula S Montenegro-MirandaVanesa Muncan

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Methods Mentioned

BETA
xenograft
column
nuclear magnetic resonance
electrophoresis
transfection
surface plasmon resonance

Software Mentioned

CHARMM
IlluminaHiseq Genomics Browser
PATHOME
Cytoscape
AutoDock Vina
- Dock
GSEA
- X
Sybyl
Surlflex

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