Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/108278
DC Field | Value | Language |
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dc.contributor.author | Soares, Joana | - |
dc.contributor.author | Espadinha, Margarida | - |
dc.contributor.author | Raimundo, Liliana | - |
dc.contributor.author | Ramos, Helena | - |
dc.contributor.author | Gomes, Ana Sara | - |
dc.contributor.author | Gomes, Sara | - |
dc.contributor.author | Loureiro, Joana B. | - |
dc.contributor.author | Inga, Alberto | - |
dc.contributor.author | Reis, Flávio | - |
dc.contributor.author | Gomes, Célia | - |
dc.contributor.author | Santos, Maria M. M. | - |
dc.contributor.author | Saraiva, Lucília | - |
dc.date.accessioned | 2023-08-22T10:27:46Z | - |
dc.date.available | 2023-08-22T10:27:46Z | - |
dc.date.issued | 2017-06 | - |
dc.identifier.issn | 15747891 | pt |
dc.identifier.uri | https://hdl.handle.net/10316/108278 | - |
dc.description.abstract | The transcription factor p53 plays a crucial role in cancer development and dissemination, and thus, p53-targeted therapies are among the most encouraging anticancer strategies. In human cancers with wild-type (wt) p53, its inactivation by interaction with murine double minute (MDM)2 and MDMX is a common event. Simultaneous inhibition of the p53 interaction with both MDMs is crucial to restore the tumor suppressor activity of p53. Here, we describe the synthesis of the new tryptophanol-derived oxazoloisoindolinone DIMP53-1 and identify its activity as a dual inhibitor of the p53-MDM2/X interactions using a yeast-based assay. DIMP53-1 caused growth inhibition, mediated by p53 stabilization and upregulation of p53 transcriptional targets involved in cell cycle arrest and apoptosis, in wt p53-expressing tumor cells, including MDM2- or MDMX-overexpressing cells. Importantly, DIMP53-1 inhibits the p53-MDM2/X interactions by potentially binding to p53, in human colon adenocarcinoma HCT116 cells. DIMP53-1 also inhibited the migration and invasion of HCT116 cells, and the migration and tube formation of HMVEC-D endothelial cells. Notably, in human tumor xenograft mice models, DIMP53-1 showed a p53-dependent antitumor activity through induction of apoptosis and inhibition of proliferation and angiogenesis. Finally, no genotoxicity or undesirable toxic effects were observed with DIMP53-1. In conclusion, DIMP53-1 is a novel p53 activator, which potentially binds to p53 inhibiting its interaction with MDM2 and MDMX. Although target-directed, DIMP53-1 has a multifunctional activity, targeting major hallmarks of cancer through its antiproliferative, proapoptotic, antiangiogenic, anti-invasive, and antimigratory properties. DIMP53-1 is a promising anticancer drug candidate and an encouraging starting point to develop improved derivatives for clinical application. | pt |
dc.language.iso | eng | pt |
dc.publisher | Wiley-Blackwell | pt |
dc.relation | This work received the financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007728 through Programa Operacional Factores de Competitividade— COMPETE) and National Funds (FCT/ MEC, Fundac ~ao para a Ci^encia e Tecnologia and Minist erio da Educac ~ao e Ci^encia) under the Partnership Agreement PT2020 UID/MULTI/04378/2013, and the project (3599-PPCDT) PTDC/DTP-FTO/ 1981/2014 – POCI-01-0145-FEDER-016581. FCT fellowships: SFRH/BD/117931/2016 (M. Espadinha), SFRH/BD/117949/2016 (L. Raimundo), PD/BD/ 114046/2015 (A.S. Gomes), SFRH/BD/96189/2013 (S. Gomes), SFRH/BD/119144/2016 (H. Ramos). | pt |
dc.rights | openAccess | pt |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt |
dc.subject | anticancer therapy | pt |
dc.subject | MDM2 | pt |
dc.subject | MDMX | pt |
dc.subject | p53 | pt |
dc.subject | small-molecule | pt |
dc.subject | tryptophanol-derived oxazoloisoindolinone | pt |
dc.subject.mesh | Angiogenesis Inhibitors | pt |
dc.subject.mesh | Animals | pt |
dc.subject.mesh | Antineoplastic Agents | pt |
dc.subject.mesh | Apoptosis | pt |
dc.subject.mesh | Cell Cycle Proteins | pt |
dc.subject.mesh | Cell Movement | pt |
dc.subject.mesh | Cell Proliferation | pt |
dc.subject.mesh | HCT116 Cells | pt |
dc.subject.mesh | Humans | pt |
dc.subject.mesh | Isoindoles | pt |
dc.subject.mesh | MCF-7 Cells | pt |
dc.subject.mesh | Mice | pt |
dc.subject.mesh | Mice, Inbred BALB C | pt |
dc.subject.mesh | Nuclear Proteins | pt |
dc.subject.mesh | Oxazoles | pt |
dc.subject.mesh | Phthalimides | pt |
dc.subject.mesh | Proto-Oncogene Proteins | pt |
dc.subject.mesh | Proto-Oncogene Proteins c-mdm2 | pt |
dc.subject.mesh | Rats | pt |
dc.subject.mesh | Rats, Wistar | pt |
dc.subject.mesh | Tumor Suppressor Protein p53 | pt |
dc.subject.mesh | Up-Regulation | pt |
dc.subject.mesh | Xenograft Model Antitumor Assays | pt |
dc.subject.mesh | Molecular Targeted Therapy | pt |
dc.title | DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties | pt |
dc.type | article | - |
degois.publication.firstPage | 612 | pt |
degois.publication.lastPage | 627 | pt |
degois.publication.issue | 6 | pt |
degois.publication.title | Molecular Oncology | pt |
dc.peerreviewed | yes | pt |
dc.identifier.doi | 10.1002/1878-0261.12051 | pt |
degois.publication.volume | 11 | pt |
dc.date.embargo | 2017-06-01 | * |
uc.date.periodoEmbargo | 0 | pt |
item.grantfulltext | open | - |
item.cerifentitytype | Publications | - |
item.languageiso639-1 | en | - |
item.openairetype | article | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | Com Texto completo | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
crisitem.author.orcid | 0000-0003-3401-9554 | - |
crisitem.author.orcid | 0000-0002-7497-4129 | - |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais I&D IBILI - Artigos em Revistas Internacionais FMUC Medicina - Artigos em Revistas Internacionais |
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DIMP53-1 A novel small-molecule dual inhibitor of p53-MDM2X interactions with multifunctional p53-dependent anticancer properties.pdf | 1.78 MB | Adobe PDF | View/Open |
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