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

Lambert, Jeremy M R and Gorzov, Petr and Veprintsev, Dimitry B and Söderqvist, Maja and Segerbäck, Dan and Bergman, Jan and Fersht, Alan R and Hainaut, Pierre and Wiman, Klas G and Bykov, Vladimir J N (2009) PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell, 15 (5). pp. 376-388. ISSN 1878-3686

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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.