Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 6, Pages 2500-2517Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01781
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Funding
- Pancreatic Cancer Research Fund
- Medical Research Council
- Wellcome Trust
- Johnson Johnson
- UCL Technology Fund
- University of Cambridge
- Cancer Research UK
- Cancer Research UK [C14303/A17197]
- Cancer Research UK Glasgow Centre
- BSU facilities at the Cancer Research UK Beatson Institute [C596/A18076, C596/A17196]
- MRC [MC_PC_12024, G1001497] Funding Source: UKRI
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Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of Gquadruplexes, using the trisubstituted naphthalene diimide quadruplexbinding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo [lmn] [3,8] phenanthroline-1,3,6,8 (2H,7H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplexbinding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.
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