PRIMA-1 reactivates mutant p53 by covalent binding to the core domain

Jeremy M R Lambert, Petr Gorzov, Dimitry B Veprintsev, Maja Söderqvist, Dan Segerbäck, Jan Bergman, Alan R Fersht, Pierre Hainaut, Klas G Wiman, Vladimir J N Bykov

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319 Citations (Scopus)


Restoration of wild-type p53 expression triggers cell death and eliminates tumors in vivo. The identification of mutant p53-reactivating small molecules such as PRIMA-1 opens possibilities for the development of more efficient anticancer drugs. Although the biological effects of PRIMA-1 are well demonstrated, little is known about its molecular mechanism of action. We show here that PRIMA-1 is converted to compounds that form adducts with thiols in mutant p53. Covalent modification of mutant p53 per se is sufficient to induce apoptosis in tumor cells. These findings might facilitate the design of more potent and specific mutant p53-targeting anticancer drugs.
Original languageEnglish
Pages (from-to)376-388
Number of pages13
JournalCancer Cell
Issue number5
Publication statusPublished - 5 May 2009


  • animals
  • tumor suppressor protein p53
  • apoptosis
  • antineoplastic agents
  • aza compounds
  • humans
  • cell line, tumor
  • mice
  • bicyclo compounds, heterocyclic
  • drug design
  • protein binding
  • neoplasms
  • protein structure, tertiary
  • mutation

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