SLMP53-2 restoreswild-type-like function to mutant p53 through hsp70: Promising activity in hepatocellular carcinoma

Sara Gomes, Bartolomeo Bosco, Joana B. Loureiro, Helena Ramos, Liliana Raimundo, Joana Soares, Nair Nazareth, Valentina Barcherini, Lucília Domingues, Carla Oliveira, Alessandra Bisio, Silvano Piazza, Matthias R. Bauer, João P. Brás, Maria Inês Almeida, Célia Gomes, Flávio Reis, Alan R. Fersht, Alberto Inga, Maria M.M. SantosLucília Saraiva

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Abstract

Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structuralmutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.

Original languageEnglish
Article number1151
JournalCancers
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2019

Keywords

  • Anticancer therapeutics
  • Hepatocellular carcinoma
  • Hsp70
  • Mutant p53
  • Tryptophanol-derived oxazoloisoindolinone

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    Gomes, S., Bosco, B., Loureiro, J. B., Ramos, H., Raimundo, L., Soares, J., Nazareth, N., Barcherini, V., Domingues, L., Oliveira, C., Bisio, A., Piazza, S., Bauer, M. R., Brás, J. P., Almeida, M. I., Gomes, C., Reis, F., Fersht, A. R., Inga, A., ... Saraiva, L. (2019). SLMP53-2 restoreswild-type-like function to mutant p53 through hsp70: Promising activity in hepatocellular carcinoma. Cancers, 11(8), [1151]. https://doi.org/10.3390/cancers11081151