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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Aza Compounds / metabolism*
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Aza Compounds / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / metabolism*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line, Tumor
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Drug Design
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Humans
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Mice
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Mutation
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / metabolism*
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Protein Binding
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Protein Structure, Tertiary
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Antineoplastic Agents
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Aza Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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Tumor Suppressor Protein p53
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2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one