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Br J Cancer. 2019 Mar;120(5):488-498. doi: 10.1038/s41416-018-0374-5. Epub 2019 Feb 22.

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

Kim JH1, Eom HJ2, Lim G3,4, Park S5,6, Lee J3,4, Nam S5,6,7, Kim YH8, Jeong JH9.

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College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Korea.
Research and Development Department, Corestem Inc., 24 Pangyo-ro, 255beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13486, Korea.
Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Korea.
Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, 21565, Korea.
College of Medicine, Gachon University, Incheon, 21565, Korea.
Department of Life Sciences, Gachon University, Seongnam, 13120, Korea.
Department of Biomedical Science, Hanyang Biomedical Research Institute, Hanyang University, Seoul, 04763, Korea.
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Korea.



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 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.


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