RRC ID 54883
Author Kim JH, Eom HJ, Lim G, Park S, Lee J, Nam S, Kim YH, Jeong JH.
Title Differential effects, on oncogenic pathway signalling, by derivatives of the HNF4 α inhibitor BI6015.
Journal Br. J. Cancer
Abstract BACKGROUND: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.
METHODS: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.
RESULTS: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.
CONCLUSION:Straightforward strategies, employing bioinformatics analyses, to facilitate the effective design and development of "druggable" transcription factor inhibitors, are useful for targeting specific oncogenic signalling pathways, in GC and other cancers.
Volume 120(5)
Pages 488-498
Published 2019-3
DOI 10.1038/s41416-018-0374-5
PII 10.1038/s41416-018-0374-5
PMID 30792535
PMC PMC6461897
IF 5.922
Human and Animal Cells MKN45(RCB1001)