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Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule.

Accepted version
Peer-reviewed

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Type

Article

Change log

Authors

Marchetti, Chiara 
Zyner, Katherine G 
Ohnmacht, Stephan A 
Robson, Mathew 
Haider, Shozeb M 

Abstract

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.

Description

Keywords

Animals, Antimetabolites, Antineoplastic, Antineoplastic Agents, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Computational Biology, Computer Simulation, DNA Damage, Deoxycytidine, Down-Regulation, Drug Design, Drug Resistance, Neoplasm, G-Quadruplexes, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Pancreatic Neoplasms, Xenograft Model Antitumor Assays, Gemcitabine

Journal Title

J Med Chem

Conference Name

Journal ISSN

0022-2623
1520-4804

Volume Title

61

Publisher

American Chemical Society (ACS)
Sponsorship
Cancer Research UK (CB4330)
Cancer Research UK (C14303/A17197)
Cancer Research UK (12488)