title: Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound.
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.
authors.affiliation: Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Vladimir J N
authors.initials: VJ
authors.lastname: Bykov
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
authors.forename: Alexandre
authors.initials: A
authors.lastname: Shilov
authors.forename: Monica
authors.initials: M
authors.lastname: Hultcrantz
authors.forename: Elena
authors.initials: E
authors.lastname: Pugacheva
authors.forename: Peter
authors.initials: P
authors.lastname: Chumakov
authors.forename: Jan
authors.initials: J
authors.lastname: Bergman
authors.forename: Klas G
authors.initials: KG
authors.lastname: Wiman
authors.forename: Galina
authors.initials: G
authors.lastname: Selivanova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001372:Aza Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D002469:Cell Separation; D005434:Flow Cytometry; D017930:Genes, Reporter; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D015394:Molecular Structure; D008970:Molecular Weight; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy; D009930:Organic Chemicals / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D015533:Transcriptional Activation / Q000187:drug effects* / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009930:Organic Chemicals; D016159:Tumor Suppressor Protein p53; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one