C Marchetti, KG Zyner, SA Ohnmacht, M Robson, SM Haider, JP Morton, G Marsico, T Vo, S Laughlin-Toth, AA Ahmed, G Di Vita, I Pazitna, M Gunaratnam, RJ Besser, ACG Andrade, S Diocou, JA Pike, D Tannahill, RB Pedley, TRJ Evans, WD Wilson, S Balasubramanian, S Neidle
Journal name: 
J Med Chem
Citation info: 
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(2 H,7 H)-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.
Research group: 
Balasubramanian Group
E-pub date: 
22 Mar 2018
Users with this publication listed: 
Carlos Caldas
David Tannahill
Emma Beddowes
Richard Baird
Shankar Balasubramanian
Stephen-John Sammut
Suet-Feung Chin