Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule

Research output: Contribution to journalArticlepeer-review

Authors

  • C Marchetti
  • KG Zyner
  • SA Ohnmacht
  • M Robson
  • SM Haider
  • JP Morton
  • G Marsico
  • T Vo
  • S Laughlin-Toth
  • AA Ahmed
  • Vita G Di
  • I Pazitna
  • M Gunaratnam
  • RJ Besser
  • ACG Andrade
  • S Diocou
  • D Tannahill
  • RB Pedley
  • TRJ Evans
  • WD Wilson
  • S Balasubramanian
  • S Neidle

Colleges, School and Institutes

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(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.

Details

Original languageEnglish
Pages (from-to)2500-2517
Number of pages18
JournalJournal of Medicinal Chemistry
Volume61
Issue number6
Early online date22 Jan 2018
Publication statusPublished - 22 Mar 2018

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