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

Marchetti, C. et al. (2018) Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a G-quadruplex-binding small molecule. Journal of Medicinal Chemistry, 61(6), pp. 2500-2517. (doi:10.1021/acs.jmedchem.7b01781) (PMID:29356532)

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Abstract

Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signalling 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 tri-substituted 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 modelling, is a potent inhibitor of cell growth in PDAC cell lines and has anti-cancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyse 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Evans, Professor Jeff and Morton, Dr Jennifer
Authors: Marchetti, C., Zyner, K. G., Ohnmacht, S. A., Robson, M., Haider, S. M., Morton, J. P., Marsico, G., Vo, T., Laughlin-Toth, S., Ahmed, A. A., Di Vita, G., Pazitna, I., Gunaratnam, M., Besser, R. J., Andrade, A. C.G., Diocou, S., Pike, J. A., Tannahill, D., Pedley, R. B., Evans, T.R. J., Wilson, W. D., Balasubramanian, S., and Neidle, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN:0022-2623
ISSN (Online):1520-4804
Published Online:22 January 2018
Copyright Holders:Copyright © 2018 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 61(6): 2500-2517
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)18076RI CANCER SCIENCES

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