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

Jin Hee Kim, Hyo Jin Eom, Gyu Tae Lim, Sungjin Park, Jinhyuk Lee, Seungyoon Nam, Yon Hui Kim, Jin Hyun Jeong

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)488-498
Number of pages11
JournalBritish journal of cancer
Issue number5
Publication statusPublished - 2019 Mar 5

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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