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

Joana Soares, Liliana Raimundo, Nuno A.L. Pereira, Ângelo Monteiro, Sara Gomes, Cláudia Bessa, Clara Pereira, Glória Queiroz, Alessandra Bisio, João Fernandes, Célia Gomes, Flávio Reis, Jorge Gonçalves, Alberto Inga, Maria M.M. Santos, Lucília Saraiva

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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 transcriptiondependent 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.

Original languageEnglish
Pages (from-to)4326-4343
Number of pages18
JournalOncotarget
Volume7
Issue number4
Early online date28 Dec 2015
DOIs
Publication statusPublished - 2016

Keywords

  • Anticancer chemotherapy
  • Mutant
  • p53
  • Tryptophanol-derived oxazoloisoindolinones
  • Tumor

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    Soares, J., Raimundo, L., Pereira, N. A. L., Monteiro, Â., Gomes, S., Bessa, C., Pereira, C., Queiroz, G., Bisio, A., Fernandes, J., Gomes, C., Reis, F., Gonçalves, J., Inga, A., Santos, M. M. M., & Saraiva, L. (2016). Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1: a novel anticancer small-molecule. Oncotarget, 7(4), 4326-4343. https://doi.org/10.18632/oncotarget.6775