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Discovery of a new small-molecule inhibitor of p53–MDM2 interaction using a yeast-based approach

2013Journal article Open access
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dc.contributor.authorLeão, Mariana
dc.contributor.authorPereira, Clara
dc.contributor.authorBisio, Alessandra
dc.contributor.authorCiribilli, Yari
dc.contributor.authorPaiva, Ana M.
dc.contributor.authorMachado, Neuza
dc.contributor.authorPalmeira, Andreia
dc.contributor.authorFernandes, Miguel X.
dc.contributor.authorSousa, Emília
dc.contributor.authorPinto, Madalena
dc.contributor.authorInga, Alberto
dc.contributor.authorSaraiva, Lucília
dc.date.accessioned2023-02-10T15:04:40Z
dc.date.available2023-02-10T15:04:40Z
dc.date.issued2013
dc.description.abstractThe virtual screening of a library of xanthone derivatives led us to the identification of potential novel MDM2 ligands. The activity of these compounds as inhibitors of p53–MDM2 interaction was investigated using a yeast phenotypic assay, herein developed for the initial screening. Using this approach, in association with a yeast p53 transactivation assay, the pyranoxanthone (3,4-dihydro-12- hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one) (1) was identified as a putative small molecule inhibitor of p53–MDM2 interaction. The activity of the pyranoxanthone 1 as inhibitor of p53–MDM2 interaction was further investigated in human tumor cells with wild-type p53 and overexpressed MDM2. Notably, the pyranoxanthone 1 mimicked the activity of known p53 activators, leading to p53 stabilization and activation of p53- dependent transcriptional activity. Additionally, it led to increased protein levels of p21 and Bax, and to caspase-7 cleavage. By computational docking studies, it was predicted that, like nutlin-3a, a known small-molecule inhibitor of p53–MDM2 interaction, pyranoxanthone 1 binds to the p53-binding site of MDM2. Overall, in this work, a novel small-molecule inhibitor of p53–MDM2 interaction with a xanthone scaffold was identified for the first time. Besides its potential use as molecular probe and possible lead to develop anticancer agents, the pyranoxanthone 1 will pave the way for the structure-based design of a new class of p53–MDM2 inhibitors.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationLeão, M., Pereira, C., Bisio, A., Ciribilli, Y., Paiva, A. M., Machado, N., ... & Saraiva, L. (2013). Discovery of a new small-molecule inhibitor of p53–MDM2 interaction using a yeast-based approach. Biochemical Pharmacology, 85(9), 1234-1245.pt_PT
dc.identifier.doi10.1016/j.bcp.2013.01.032pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.13/5027
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationStrategic Project - LA 6 - 2011-2012
dc.relationStrategic Project - UI 4040 - 2011-2012
dc.relationUSING YEAST CELL-BASED SYSTEMS FOR FUNCTIONAL AND MOLECULAR STUDIES OF P53 FAMILY ISOFORMS: SCREENING FOR SMALL-MOLECULE MODULATORS
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectXanthone derivativespt_PT
dc.subjectInhibitor of p53–MDM2 interactionpt_PT
dc.subjectComputational dockingpt_PT
dc.subjectYeast-based assayspt_PT
dc.subjectAntitumor activitypt_PT
dc.subject.pt_PT
dc.subjectFaculdade de Ciências Exatas e da Engenhariapt_PT
dc.titleDiscovery of a new small-molecule inhibitor of p53–MDM2 interaction using a yeast-based approachpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleStrategic Project - LA 6 - 2011-2012
oaire.awardTitleStrategic Project - UI 4040 - 2011-2012
oaire.awardTitleUSING YEAST CELL-BASED SYSTEMS FOR FUNCTIONAL AND MOLECULAR STUDIES OF P53 FAMILY ISOFORMS: SCREENING FOR SMALL-MOLECULE MODULATORS
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6820 - DCRRNI ID/PEst-C%2FEQB%2FLA0006%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FSAU%2FUI4040%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F64184%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-FCF%2F100930%2F2008/PT
oaire.citation.endPage1245pt_PT
oaire.citation.issue9pt_PT
oaire.citation.startPage1234pt_PT
oaire.citation.titleBiochemical Pharmacologypt_PT
oaire.citation.volume85pt_PT
oaire.fundingStream6820 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream5876-PPCDTI
person.familyNameFernandes
person.givenNameMiguel Xavier
person.identifier.ciencia-idED1D-3C7A-467C
person.identifier.orcid0000-0002-1840-616X
person.identifier.ridA-4373-2013
person.identifier.scopus-author-id35466972500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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