dc.contributor.author | Te Lintel Hekkert, M | |
dc.contributor.author | Newton, G | |
dc.contributor.author | Chapman, K | |
dc.contributor.author | Aqil, R | |
dc.contributor.author | Downham, R | |
dc.contributor.author | Yan, R | |
dc.contributor.author | Merkus, D | |
dc.contributor.author | Whitlock, G | |
dc.contributor.author | Lane, CAL | |
dc.contributor.author | Cawkill, D | |
dc.contributor.author | Perrior, T | |
dc.contributor.author | Duncker, DJ | |
dc.contributor.author | Schneider, MD | |
dc.date.accessioned | 2021-06-03T09:40:46Z | |
dc.date.available | 2021-06-03T09:40:46Z | |
dc.date.issued | 2021-05-20 | |
dc.identifier.citation | Basic research in cardiology, 2021, 116 (1), pp. 34 - ? | |
dc.identifier.issn | 0300-8428 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4598 | |
dc.identifier.eissn | 1435-1803 | |
dc.identifier.doi | 10.1007/s00395-021-00875-7 | |
dc.description.abstract | Reducing 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.format | Electronic | |
dc.format.extent | 34 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | SPRINGER HEIDELBERG | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Preclinical 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.type | Journal Article | |
dcterms.dateAccepted | 2021-04-19 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1007/s00395-021-00875-7 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-05-20 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Basic research in cardiology | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 116 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 3 | |
icr.researchteam | Medicinal Chemistry 3 | |
dc.contributor.icrauthor | Newton, Gary | |