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dc.contributor.authorIbbeson, Brett Men
dc.contributor.authorLaraia, Lucaen
dc.contributor.authorAlza, Estheren
dc.contributor.authorO'Connor, Cornelius Jen
dc.contributor.authorTan, Yaw Singen
dc.contributor.authorDavies, Huw MLen
dc.contributor.authorMcKenzie, Grahameen
dc.contributor.authorVenkitaraman, Ashoken
dc.contributor.authorSpring, Daviden
dc.date.accessioned2014-09-16T16:20:12Z
dc.date.available2014-09-16T16:20:12Z
dc.date.issued2014-01-17en
dc.identifier.citation(2014) Nature Communications 5: 3155en
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/245944
dc.description.abstractThe synthesis of diverse 3-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis (DOS) of a compound library using rhodium carbenoid chemistry to access structurally diverse, 3-dimensional molecules, and show that they access biologically relevant areas of chemical space using cheminformatic analysis. High content screening (HCS) of this library for anti-mitotic activity, followed by chemical modification identified ‘Dosabulin’, which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect Vinblastine binding to tubulin, however experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of DOS and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.
dc.languageen_USen
dc.language.isoen_USen
dc.publisherNPG
dc.titleDiversity-oriented synthesis as a tool for identifying new modulators of mitosisen
dc.typeArticle
dc.description.versionThis is the author's accepted manuscript. The final version was published in Nature Communications here: http://www.nature.com/ncomms/2014/140117/ncomms4155/full/ncomms4155.html#affil-auth.en
prism.publicationDate2014en
prism.publicationNameNature Communicationsen
prism.startingPage3155
prism.volume5en
dc.rioxxterms.funderEuropean Union European Research Council Engineering and Physical Sciences Research Council Cancer Research UK Biotechnology and Biological Sciences Research Council Medical Research Council Wellcome Trust A*STAR Frances and Augustus Newman foundation
dcterms.dateAccepted2013-12-18en
rioxxterms.versionofrecord10.1038/ncomms4155en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2014-01-17en
dc.contributor.orcidSpring, David [0000-0001-7355-2824]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (G1001521)
pubs.funder-project-idMRC (MC_UU_12022/8)
pubs.funder-project-idMedical Research Council (MC_UU_12022/1)
pubs.funder-project-idEPSRC (EP/J016012/1)
pubs.funder-project-idRoyal Society (WM150022)
pubs.funder-project-idEuropean Research Council (279337)
pubs.funder-project-idWellcome Trust (090340/Z/09/Z)
pubs.funder-project-idMRC (MC_UU_12022/8)


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