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dc.contributor.authorMarchetti, Chiaraen
dc.contributor.authorZyner, Katherine Gen
dc.contributor.authorOhnmacht, Stephan Aen
dc.contributor.authorRobson, Mathewen
dc.contributor.authorHaider, Shozeb Men
dc.contributor.authorMorton, Jennifer Pen
dc.contributor.authorMarsico, Giovannien
dc.contributor.authorVo, Tamen
dc.contributor.authorLaughlin-Toth, Sarahen
dc.contributor.authorAhmed, Ahmed Aen
dc.contributor.authorDi Vita, Gloriaen
dc.contributor.authorPazitna, Ingridaen
dc.contributor.authorGunaratnam, Mekalaen
dc.contributor.authorBesser, Rachael Jen
dc.contributor.authorAndrade, Ana CGen
dc.contributor.authorDiocou, Seckouen
dc.contributor.authorPike, Jeremy Aen
dc.contributor.authorTannahill, Daviden
dc.contributor.authorPedley, R Barbaraen
dc.contributor.authorEvans, TR Jeffryen
dc.contributor.authorWilson, W Daviden
dc.contributor.authorBalasubramanian, Shankaren
dc.contributor.authorNeidle, Stephenen
dc.date.accessioned2018-03-26T08:41:40Z
dc.date.available2018-03-26T08:41:40Z
dc.date.issued2018-03en
dc.identifier.issn0022-2623
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/274321
dc.description.abstractHuman 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.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherAmerican Chemical Society
dc.subjectCell Line, Tumoren
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectMice, Nudeen
dc.subjectCarcinoma, Pancreatic Ductalen
dc.subjectPancreatic Neoplasmsen
dc.subjectDNA Damageen
dc.subjectDeoxycytidineen
dc.subjectAntineoplastic Agentsen
dc.subjectAntimetabolites, Antineoplasticen
dc.subjectXenograft Model Antitumor Assaysen
dc.subjectComputational Biologyen
dc.subjectDown-Regulationen
dc.subjectGene Expression Regulation, Neoplasticen
dc.subjectDrug Designen
dc.subjectDrug Resistance, Neoplasmen
dc.subjectComputer Simulationen
dc.subjectG-Quadruplexesen
dc.titleTargeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule.en
dc.typeArticle
prism.endingPage2517
prism.issueIdentifier6en
prism.publicationDate2018en
prism.publicationNameJournal of medicinal chemistryen
prism.startingPage2500
prism.volume61en
dc.identifier.doi10.17863/CAM.21443
dcterms.dateAccepted2018-01-22en
rioxxterms.versionofrecord10.1021/acs.jmedchem.7b01781en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-03en
dc.contributor.orcidZyner, Katherine G [0000-0002-4997-0150]
dc.contributor.orcidHaider, Shozeb M [0000-0003-2650-2925]
dc.contributor.orcidMorton, Jennifer P [0000-0001-5766-9141]
dc.contributor.orcidAhmed, Ahmed A [0000-0002-0409-7589]
dc.contributor.orcidPike, Jeremy A [0000-0003-4163-0335]
dc.contributor.orcidTannahill, David [0000-0002-3811-6864]
dc.contributor.orcidBalasubramanian, Shankar [0000-0002-0281-5815]
dc.contributor.orcidNeidle, Stephen [0000-0003-0622-6548]
dc.identifier.eissn1520-4804
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (CB4330)
pubs.funder-project-idCancer Research UK (C14303_do not transfer)
rioxxterms.freetoread.startdate2019-01-22


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