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

  • Soares J
  • Raimundo L
  • Pereira N
  • et al.
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Abstract

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.

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APA

Soares, J., Raimundo, L., Pereira, N. A. L., Monteiro, Â., Gomes, S., Bessa, C., … Saraiva, L. (2015). Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule. Oncotarget, 7(4). https://doi.org/10.18632/oncotarget.6775

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