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dc.contributor.authorIbbeson, Brett M
dc.contributor.authorLaraia, Luca
dc.contributor.authorAlza, Esther
dc.contributor.authorO' Connor, Cornelius J
dc.contributor.authorTan, Yaw Sing
dc.contributor.authorDavies, Huw ML
dc.contributor.authorMcKenzie, Grahame
dc.contributor.authorVenkitaraman, Ashok R
dc.contributor.authorSpring, David R
dc.date.accessioned2014-09-16T16:20:12Z
dc.date.available2014-09-16T16:20:12Z
dc.date.issued2014
dc.identifier.citation(2014) Nature Communications 5: 3155
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/245944
dc.description.abstractThe synthesis of diverse three-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 of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. High-content screening of this library for antimitotic 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 diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.
dc.languageen_US
dc.language.isoen_US
dc.publisherSpringer Science and Business Media LLC
dc.titleDiversity-oriented synthesis as a tool for identifying new modulators of mitosis.
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.
prism.publicationDate2014
prism.publicationNameNat Commun
prism.startingPage3155
prism.volume5
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.dateAccepted2013-12-18
rioxxterms.versionofrecord10.1038/ncomms4155
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2014-01-17
dc.contributor.orcidSpring, David [0000-0001-7355-2824]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (G1001521)
pubs.funder-project-idMedical Research Council (G1001522)
pubs.funder-project-idMedical Research Council (MC_UU_12022/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (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)
cam.issuedOnline2014-01-17


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