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https://hdl.handle.net/10316/108278
Título: | DIMP53-1: a novel small-molecule dual inhibitor of p53-MDM2/X interactions with multifunctional p53-dependent anticancer properties | Autor: | Soares, Joana Espadinha, Margarida Raimundo, Liliana Ramos, Helena Gomes, Ana Sara Gomes, Sara Loureiro, Joana B. Inga, Alberto Reis, Flávio Gomes, Célia Santos, Maria M. M. Saraiva, Lucília |
Palavras-chave: | anticancer therapy; MDM2; MDMX; p53; small-molecule; tryptophanol-derived oxazoloisoindolinone | Data: | Jun-2017 | Editora: | Wiley-Blackwell | Projeto: | POCI/01/0145/FEDER/00772 UID/Multi/04378/2013 (UCIBIO/REQUIMTE) POCI-01-0145-FEDER-016581 SFRH/BD/117931/2016 SFRH/BD/117949/2016 PD/BD/114046/2015 SFRH/BD/96189/2013 SFRH/BD/119144/2016 |
Título da revista, periódico, livro ou evento: | Molecular Oncology | Volume: | 11 | Número: | 6 | Resumo: | 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. | URI: | https://hdl.handle.net/10316/108278 | ISSN: | 15747891 | DOI: | 10.1002/1878-0261.12051 | Direitos: | openAccess |
Aparece nas coleções: | 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 | Ver/Abrir |
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