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dc.contributor.authorTe Lintel Hekkert, M
dc.contributor.authorNewton, G
dc.contributor.authorChapman, K
dc.contributor.authorAqil, R
dc.contributor.authorDownham, R
dc.contributor.authorYan, R
dc.contributor.authorMerkus, D
dc.contributor.authorWhitlock, G
dc.contributor.authorLane, CAL
dc.contributor.authorCawkill, D
dc.contributor.authorPerrior, T
dc.contributor.authorDuncker, DJ
dc.contributor.authorSchneider, MD
dc.date.accessioned2021-06-03T09:40:46Z
dc.date.available2021-06-03T09:40:46Z
dc.date.issued2021-05-20
dc.identifier.citationBasic research in cardiology, 2021, 116 (1), pp. 34 - ?
dc.identifier.issn0300-8428
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4598
dc.identifier.eissn1435-1803
dc.identifier.doi10.1007/s00395-021-00875-7
dc.description.abstractReducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.
dc.formatElectronic
dc.format.extent34 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titlePreclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals?
dc.typeJournal Article
dcterms.dateAccepted2021-04-19
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1007/s00395-021-00875-7
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-05-20
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBasic research in cardiology
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.publication-statusPublished
pubs.volume116en_US
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 3
icr.researchteamMedicinal Chemistry 3en_US
dc.contributor.icrauthorNewton, Garyen


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