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

doi:10.1016/j.ccr.2009.03.003

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

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

479 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.

Original language	English
Pages (from-to)	376-388
Number of pages	13
Journal	Cancer Cell
Volume	15
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2009.03.003
Publication status	Published - 5 May 2009

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2009.03.003

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title = "PRIMA-1 reactivates mutant p53 by covalent binding to the core domain",

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.",

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",

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AU - Lambert, Jeremy M R

AU - Gorzov, Petr

AU - Veprintsev, Dimitry B

AU - Söderqvist, Maja

AU - Segerbäck, Dan

AU - Bergman, Jan

AU - Fersht, Alan R

AU - Hainaut, Pierre

AU - Wiman, Klas G

AU - Bykov, Vladimir J N

PY - 2009/5/5

Y1 - 2009/5/5

N2 - 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.

AB - 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.

KW - animals

KW - tumor suppressor protein p53

KW - apoptosis

KW - antineoplastic agents

KW - aza compounds

KW - humans

KW - cell line, tumor

KW - mice

KW - bicyclo compounds, heterocyclic

KW - drug design

KW - protein binding

KW - neoplasms

KW - protein structure, tertiary

KW - mutation

UR - http://www.cell.com/cancer-cell/home

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DO - 10.1016/j.ccr.2009.03.003

M3 - Article

C2 - 19411067

SN - 1878-3686

VL - 15

SP - 376

EP - 388

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Keywords

UN SDGs

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