Reference - Detail
| 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 | 2019-3-1 |
| DOI | 10.1038/s41416-018-0374-5 |
| PII | 10.1038/s41416-018-0374-5 |
| PMID | 30792535 |
| PMC | PMC6461897 |
| MeSH | Benzimidazoles / pharmacology* Cell Line, Tumor Drug Discovery Hepatocyte Nuclear Factor 4 / antagonists & inhibitors* Humans Molecular Docking Simulation Signal Transduction Stomach Neoplasms / metabolism* Substrate Specificity Sulfonamides / pharmacology* Surface Plasmon Resonance Wnt Proteins / drug effects* Wnt Proteins / metabolism |
| IF | 5.416 |
| Times Cited | 5 |
| Resource | |
| Human and Animal Cells | MKN45(RCB1001) |