Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Vladimir J N Bykov; Natalia Issaeva; Alexandre Shilov; Monica Hultcrantz; Elena Pugacheva; Peter Chumakov; Jan Bergman; Klas G Wiman; Galina Selivanova

doi:10.1038/nm0302-282

Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound

Nat Med. 2002 Mar;8(3):282-8. doi: 10.1038/nm0302-282.

Authors

Vladimir J N Bykov¹, Natalia Issaeva, Alexandre Shilov, Monica Hultcrantz, Elena Pugacheva, Peter Chumakov, Jan Bergman, Klas G Wiman, Galina Selivanova

Affiliation

¹ Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.

PMID: 11875500
DOI: 10.1038/nm0302-282

Abstract

The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. Mutations in p53 occur in at least 50% of human tumors. We hypothesized that reactivation of mutant p53 in such tumors should trigger massive apoptosis and eliminate the tumor cells. To test this, we screened a library of low-molecular-weight compounds in order to identify compounds that can restore wild-type function to mutant p53. We found one compound capable of inducing apoptosis in human tumor cells through restoration of the transcriptional transactivation function to mutant p53. This molecule, named PRIMA-1, restored sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. PRIMA-1 rescued both DNA contact and structural p53 mutants. In vivo studies in mice revealed an antitumor effect with no apparent toxicity. This molecule may serve as a lead compound for the development of anticancer drugs targeting mutant p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects*
Apoptosis / physiology
Aza Compounds / pharmacology*
Aza Compounds / therapeutic use
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Cell Separation
Flow Cytometry
Genes, Reporter
Humans
In Situ Nick-End Labeling
Mice
Molecular Structure
Molecular Weight
Mutation
Neoplasms / drug therapy
Organic Chemicals / pharmacology*
Organic Chemicals / therapeutic use
Protein Conformation
Transcriptional Activation / drug effects*
Transcriptional Activation / physiology
Transplantation, Heterologous
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / physiology*

Substances

Antineoplastic Agents
Aza Compounds
Bridged Bicyclo Compounds, Heterocyclic
Organic Chemicals
Tumor Suppressor Protein p53
2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one