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

Title
Reactivation of wild-type and mutant p53 by tryptophanol-derived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule
Type
Article in International Scientific Journal
Year
2016
Authors
Soares, J
(Author)
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Raimundo, L
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Pereira, NAL
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Monteiro, A
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Gomes, S
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Bessa, C
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Pereira, C
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Queiroz, G
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FFUP
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Bisio, A
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Fernandes, J
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Gomes, C
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Reis, F
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Goncalves, J
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Inga, A
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Santos, MMM
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Lucilia Saraiva
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FFUP
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Journal
Title: OncotargetImported from Authenticus Search for Journal Publications
Vol. 7
Pages: 4326-4343
ISSN: 1949-2553
Publisher: Impact Journals
Scientific classification
CORDIS: Health sciences
FOS: Medical and Health sciences
Other information
Authenticus ID: P-00K-5ZP
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.
Language: English
Type (Professor's evaluation): Scientific
No. of pages: 18
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