title: Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator.
abstract: We have carried out a cell-based screen aimed at discovering small molecules that activate p53 and have the potential to decrease tumor growth. Here, we describe one of our hit compounds, tenovin-1, along with a more water-soluble analog, tenovin-6. Via a yeast genetic screen, biochemical assays, and target validation studies in mammalian cells, we show that tenovins act through inhibition of the protein-deacetylating activities of SirT1 and SirT2, two important members of the sirtuin family. Tenovins are active on mammalian cells at one-digit micromolar concentrations and decrease tumor growth in vivo as single agents. This underscores the utility of these compounds as biological tools for the study of sirtuin function as well as their potential therapeutic interest.
authors.affiliation: Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK. s.lain@dundee.ac.uk
authors.forename: Sonia
authors.initials: S
authors.lastname: Lain
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hollick
authors.forename: Johanna
authors.initials: J
authors.lastname: Campbell
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Staples
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.forename: Mustapha
authors.initials: M
authors.lastname: Aoubala
authors.forename: Anna
authors.initials: A
authors.lastname: McCarthy
authors.forename: Virginia
authors.initials: V
authors.lastname: Appleyard
authors.forename: Karen E
authors.initials: KE
authors.lastname: Murray
authors.forename: Lee
authors.initials: L
authors.lastname: Baker
authors.forename: Alastair
authors.initials: A
authors.lastname: Thompson
authors.forename: Joanne
authors.initials: J
authors.lastname: Mathers
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Holland
authors.forename: Michael J R
authors.initials: MJ
authors.lastname: Stark
authors.forename: Georgia
authors.initials: G
authors.lastname: Pass
authors.forename: Julie
authors.initials: J
authors.lastname: Woods
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Westwood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008322:Mammals; D008954:Models, Biological; D012441:Saccharomyces cerevisiae / Q000502:physiology; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins / Q000502:physiology; D019063:Tenascin / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019063:Tenascin; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins