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
  • 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.