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Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

2016-12Journal article Open Access
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dc.contributor.authorCautain, Bastien
dc.contributor.authorCastillo, Francisco
dc.contributor.authorMusso, Loana
dc.contributor.authorFerreira, Bibiana
dc.contributor.authorde Pedro, Nuria
dc.contributor.authorQuesada, Lorena Rodriguez
dc.contributor.authorMachado, Susana
dc.contributor.authorVicente, Francisca
dc.contributor.authorDallavalle, Sabrina
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2017-04-07T15:55:35Z
dc.date.available2017-04-07T15:55:35Z
dc.date.issued2016-12
dc.description.abstractFOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines.
dc.identifier.doi10.1371/journal.pone.0167491
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.1/9165
dc.language.isoeng
dc.peerreviewedyes
dc.relationCharacterizing the clinical relevance of TRIB2 mediated resistance to PI3K pathway inhibition in colon and breast cancer
dc.relation.isbasedonWOS:000389587100109
dc.titleDiscovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCharacterizing the clinical relevance of TRIB2 mediated resistance to PI3K pathway inhibition in colon and breast cancer
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FBIM%2F04773%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F100434%2F2014/PT
oaire.citation.endPagee0167491
oaire.citation.issue12
oaire.citation.startPagee0167491
oaire.citation.titlePlos One
oaire.citation.volume11
oaire.fundingStream5876
oaire.fundingStreamOE
person.familyNameferreira
person.familyNameMachado
person.familyNameLink
person.givenNameBibiana
person.givenNameSusana
person.givenNameWolfgang
person.identifier803637
person.identifier.ciencia-idA311-E925-09C5
person.identifier.ciencia-id6910-952E-242A
person.identifier.orcid0000-0003-4772-9395
person.identifier.orcid0000-0002-3152-1701
person.identifier.orcid0000-0002-3340-5165
person.identifier.ridK-4033-2012
person.identifier.scopus-author-id56201414700
person.identifier.scopus-author-id35368713800
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
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicationc928b692-bf43-4e45-929b-cba3517a966d
relation.isAuthorOfPublication4972e808-7782-4cec-8d31-ab48a5899648
relation.isAuthorOfPublication12535e25-d71b-4a7f-9fc9-fff42d47deaf
relation.isAuthorOfPublication.latestForDiscovery4972e808-7782-4cec-8d31-ab48a5899648
relation.isProjectOfPublicatione13142f2-37b8-4b5a-b2cd-352e62003184
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