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dc.contributor.authorGomes, Sara
dc.contributor.authorBosco, Bartolomeo
dc.contributor.authorLoureiro, Joana B
dc.contributor.authorRamos, Helena
dc.contributor.authorRaimundo, Liliana
dc.contributor.authorSoares, Joana
dc.contributor.authorNazareth, Nair
dc.contributor.authorBarcherini, Valentina
dc.contributor.authorDomingues, Lucília
dc.contributor.authorOliveira, Carla
dc.contributor.authorBisio, Alessandra
dc.contributor.authorPiazza, Silvano
dc.contributor.authorBauer, Matthias R
dc.contributor.authorBrás, João P
dc.contributor.authorAlmeida, Maria Inês
dc.contributor.authorGomes, Célia
dc.contributor.authorReis, Flávio
dc.contributor.authorFersht, Alan
dc.contributor.authorInga, Alberto
dc.contributor.authorSantos, Maria MM
dc.contributor.authorSaraiva, Lucília
dc.date.accessioned2019-10-29T00:30:52Z
dc.date.available2019-10-29T00:30:52Z
dc.date.issued2019-08-10
dc.identifier.issn2072-6694
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/298123
dc.description.abstractHalf of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.
dc.format.mediumElectronic
dc.languageeng
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleSLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma.
dc.typeArticle
prism.issueIdentifier8
prism.publicationDate2019
prism.publicationNameCancers (Basel)
prism.volume11
dc.identifier.doi10.17863/CAM.45180
dcterms.dateAccepted2019-08-07
rioxxterms.versionofrecord10.3390/cancers11081151
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-08-10
dc.contributor.orcidRamos, Helena [0000-0001-5546-9998]
dc.contributor.orcidRaimundo, Liliana [0000-0001-9003-2601]
dc.contributor.orcidDomingues, Lucília [0000-0003-1089-7627]
dc.contributor.orcidPiazza, Silvano [0000-0002-7156-5434]
dc.contributor.orcidBauer, Matthias R [0000-0003-4015-6483]
dc.contributor.orcidBrás, João P [0000-0003-1867-0486]
dc.contributor.orcidAlmeida, Maria Inês [0000-0003-2072-8587]
dc.contributor.orcidReis, Flávio [0000-0003-3401-9554]
dc.contributor.orcidInga, Alberto [0000-0002-8767-1637]
dc.contributor.orcidSantos, Maria MM [0000-0002-2239-9353]
dc.contributor.orcidSaraiva, Lucília [0000-0002-9531-4939]
dc.identifier.eissn2072-6694
rioxxterms.typeJournal Article/Review
cam.issuedOnline2019-08-10


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