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

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

  • J Med Chem. 2018 Mar 22;61(6):2500-2517. doi: 10.1021/acs.jmedchem.7b01781.
Chiara Marchetti 1,  Katherine G Zyner 2,  Stephan A Ohnmacht 1,  Mathew Robson 3,  Shozeb M Haider 1,  Jennifer P Morton 4 5,  Giovanni Marsico 2,  Tam Vo 6,  Sarah Laughlin-Toth 6,  Ahmed A Ahmed 1,  Gloria Di Vita 1,  Ingrida Pazitna 1,  Mekala Gunaratnam 1,  Rachael J Besser 1,  Ana C G Andrade 1,  Seckou Diocou 7,  Jeremy A Pike 2,  David Tannahill 2,  R Barbara Pedley 7,  T R Jeffry Evans 4 5,  W David Wilson 6,  Shankar Balasubramanian 2 8 9,  Stephen Neidle 1
Affiliations

Affiliations

  • 1 UCL School of Pharmacy , University College London , 29-39 Brunswick Square , London WC1N 1AX , U.K.
  • 2 Cancer Research UK , Cambridge Research Institute , Li Ka Shing Centre, Robinson Way , Cambridge CB2 0RE , U.K.
  • 3 Cancer Research UK Cancer Centre, UCL Cancer Institute , University College London , London WC1E 6BT , U.K.
  • 4 Cancer Research UK , Beatson Institute , Garscube Estate, Switchback Road , Glasgow G61 1BD U.K.
  • 5 Institute of Cancer Sciences . University of Glasgow , Glasgow G12 8QQ , U.K.
  • 6 Department of Chemistry and Center for Biotechnology and Drug Design , Georgia State University , Atlanta , Georgia 30303-3083 , United States.
  • 7 UCL Cancer Institute , University College London , London WC1E 6BT , U.K.
  • 8 Department of Chemistry , University of Cambridge , Cambridge CB2 1EW , U.K.
  • 9 The School of Clinical Medicine , University of Cambridge , Cambridge CB2 0SP , U.K.
PMID: 29356532 DOI: 10.1021/acs.jmedchem.7b01781
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.

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