Reactivation of wild-type and mutant p53 by tryptophanol-derived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule

• Tipo: Artigo em Revista Científica Internacional
• Data: 2016

Autores

Soares, J (Autor) Outra; Raimundo, L (Autor) Outra; Pereira, NAL (Autor) Outra; Monteiro, A (Autor) Outra; Gomes, S (Autor) Outra; Bessa, C (Autor) Outra; Pereira, C (Autor) Outra; Queiroz, G (Autor) FFUP; Bisio, A (Autor) Outra; Fernandes, J (Autor) Outra; Gomes, C (Autor) Outra; Reis, F (Autor) Outra; Goncalves, J (Autor) Outra; Inga, A (Autor) Outra; Santos, MMM (Autor) Outra; Lucilia Saraiva (Autor) FFUP

Revista

Título: Oncotarget

Vol. 7

Páginas: 4326-4343

ISSN: 1949-2553

Editora: Impact Journals

Indexação

ISI Web of Knowledge - 35 Citações

Scopus - 35 Citações

Classificação Científica

CORDIS: Ciências da Saúde

FOS: Ciências médicas e da saúde

Outras Informações

ID Authenticus: P-00K-5ZP

DOI: 10.18632/oncotarget.6775

Abstract (EN): Restoration of the p53 pathway, namely by reactivation of mutant (mut) p53, represents a valuable anticancer strategy. Herein, we report the identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type (wt) and mut p53, using a yeast-based screening strategy. SLMP53-1 has a p53-dependent anti-proliferative activity in human wt and mut p53R280K-expressing tumor cells. Additionally, SLMP53-1 enhances p53 transcriptional activity and restores wt-like DNA binding ability to mut p53R280K. In wt/mut p53-expressing tumor cells, SLMP53-1 triggers p53 transcription-dependent and mitochondrial apoptotic pathways involving BAX, and wt/mut p53 mitochondrial translocation. SLMP53-1 inhibits the migration of wt/mut p53-expressing tumor cells, and it shows promising p53-dependent synergistic effects with conventional chemotherapeutics. In xenograft mice models, SLMP53-1 inhibits the growth of wt/mut p53-expressing tumors, but not of p53-null tumors, without apparent toxicity. Collectively, besides the potential use of SLMP53-1 as anticancer drug, the tryptophanol-derived oxazoloisoindolinone scaffold represents a promissing starting point for the development of effective p53-reactivating drugs.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 18