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dc.contributor.authorStephenson, Zoe A
dc.contributor.authorHarvey, Robert F
dc.contributor.authorPryde, Kenneth R
dc.contributor.authorMistry, Sarah
dc.contributor.authorHardy, Rachel E
dc.contributor.authorSerreli, Riccardo
dc.contributor.authorChung, Injae
dc.contributor.authorAllen, Timothy EH
dc.contributor.authorStoneley, Mark
dc.contributor.authorMacFarlane, Marion
dc.contributor.authorFischer, Peter M
dc.contributor.authorHirst, Judy
dc.contributor.authorKellam, Barrie
dc.contributor.authorWillis, Anne E
dc.date.accessioned2020-06-26T05:01:47Z
dc.date.available2020-06-26T05:01:47Z
dc.date.issued2020-05-20
dc.date.submitted2020-02-07
dc.identifier.other55845
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/307294
dc.description.abstractDisruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch Article
dc.subjectBiochemistry and Chemical Biology
dc.subjectCancer Biology
dc.subjecttoxicophore
dc.subjectmitochondria
dc.subjectcardiac liability
dc.subjectHuman
dc.titleIdentification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
dc.typeArticle
dc.date.updated2020-06-26T05:01:46Z
prism.publicationNameeLife
prism.volume9
dc.identifier.doi10.17863/CAM.54391
dcterms.dateAccepted2020-05-20
rioxxterms.versionofrecord10.7554/elife.55845
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Topisirovic, Ivan
datacite.contributor.supervisorsenior_editor: Cole, Philip A
dc.contributor.orcidHarvey, Robert F [0000-0002-0023-1146]
dc.contributor.orcidChung, Injae [0000-0002-2902-4677]
dc.contributor.orcidHirst, Judy [0000-0001-8667-6797]
dc.contributor.orcidKellam, Barrie [0000-0003-0030-9908]
dc.contributor.orcidWillis, Anne E [0000-0002-1470-8531]
dc.identifier.eissn2050-084X
pubs.funder-project-idMedical Research Council (MC_UU_000 /RG94521)
pubs.funder-project-idMedical Research Council (PUAG015)
pubs.funder-project-idMedical Research Council (MC_U105663141)
pubs.funder-project-idMedical Research Council (MC_UU_00015/2)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)