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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 61; no. 6; pp. 2500 - 2517
Main Authors:	Marchetti, Chiara, Zyner, Katherine G, Ohnmacht, Stephan A, Robson, Mathew, Haider, Shozeb M, Morton, Jennifer P, Marsico, Giovanni, Vo, Tam, Laughlin-Toth, Sarah, Ahmed, Ahmed A, Di Vita, Gloria, Pazitna, Ingrida, Gunaratnam, Mekala, Besser, Rachael J, Andrade, Ana C. G, Diocou, Seckou, Pike, Jeremy A, Tannahill, David, Pedley, R. Barbara, Evans, T. R. Jeffry, Wilson, W. David, Balasubramanian, Shankar, Neidle, Stephen
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 22-03-2018
Subjects:	Animals Antimetabolites, Antineoplastic - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - genetics Cell Line, Tumor Computational Biology Computer Simulation Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology DNA Damage Down-Regulation - drug effects Drug Design Drug Resistance, Neoplasm G-Quadruplexes Gemcitabine Gene Expression Regulation, Neoplastic - drug effects Humans Mice Mice, Nude Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Xenograft Model Antitumor Assays
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.7b01781