American Chemical Society
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Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G‑Quadruplex-Binding Small Molecule

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posted on 2018-01-22, 00:00 authored by Chiara Marchetti, Katherine G. Zyner, Stephan A. Ohnmacht, Mathew Robson, Shozeb M. Haider, Jennifer P. Morton, Giovanni Marsico, Tam Vo, Sarah Laughlin-Toth, Ahmed A. Ahmed, Gloria Di Vita, Ingrida Pazitna, Mekala Gunaratnam, Rachael J. Besser, Ana C. G. Andrade, Seckou Diocou, Jeremy A. Pike, David Tannahill, R. Barbara Pedley, T. R. Jeffry Evans, W. David Wilson, Shankar Balasubramanian, Stephen Neidle
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 G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding 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 quadruplex-binding 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.