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

Research output: Contribution to journalArticle

253 Citations (Scopus)

Abstract

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.
LanguageEnglish
Pages376-388
Number of pages13
JournalCancer Cell
Volume15
Issue number5
DOIs
Publication statusPublished - 5 May 2009

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Drug Delivery Systems
Sulfhydryl Compounds
Neoplasms
Cell Death
Apoptosis
Pharmaceutical Preparations
2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one

Keywords

  • 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

Cite this

Lambert, J. M. R., Gorzov, P., Veprintsev, D. B., Söderqvist, M., Segerbäck, D., Bergman, J., ... Bykov, V. J. N. (2009). PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell, 15(5), 376-388. https://doi.org/10.1016/j.ccr.2009.03.003
Lambert, Jeremy M R ; Gorzov, Petr ; Veprintsev, Dimitry B ; Söderqvist, Maja ; Segerbäck, Dan ; Bergman, Jan ; Fersht, Alan R ; Hainaut, Pierre ; Wiman, Klas G ; Bykov, Vladimir J N. / PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. In: Cancer Cell. 2009 ; Vol. 15, No. 5. pp. 376-388.
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Lambert, JMR, Gorzov, P, Veprintsev, DB, Söderqvist, M, Segerbäck, D, Bergman, J, Fersht, AR, Hainaut, P, Wiman, KG & Bykov, VJN 2009, 'PRIMA-1 reactivates mutant p53 by covalent binding to the core domain' Cancer Cell, vol. 15, no. 5, pp. 376-388. https://doi.org/10.1016/j.ccr.2009.03.003

PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. / Lambert, Jeremy M R; Gorzov, Petr; Veprintsev, Dimitry B; Söderqvist, Maja; Segerbäck, Dan; Bergman, Jan; Fersht, Alan R; Hainaut, Pierre; Wiman, Klas G; Bykov, Vladimir J N.

In: Cancer Cell, Vol. 15, No. 5, 05.05.2009, p. 376-388.

Research output: Contribution to journalArticle

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Lambert JMR, Gorzov P, Veprintsev DB, Söderqvist M, Segerbäck D, Bergman J et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009 May 5;15(5):376-388. https://doi.org/10.1016/j.ccr.2009.03.003