Author/Authors :
Lain، نويسنده , , Sonia and Hollick، نويسنده , , Jonathan J. and Campbell، نويسنده , , Johanna and Staples، نويسنده , , Oliver D. and Higgins، نويسنده , , Maureen and Aoubala، نويسنده , , Mustapha and McCarthy، نويسنده , , Anna and Appleyard، نويسنده , , Virginia and Murray، نويسنده , , Karen E. and Baker، نويسنده , , Lee and Thompson، نويسنده , , Alastair and Mathers، نويسنده , , Joanne M. Holland، نويسنده , , Stephen J. and Stark، نويسنده , , Michael J.R. and Pass، نويسنده , , Georgia and Woods، نويسنده , , Julie D. Lane، نويسنده , , David P. and Westwood، نويسنده , , Nicholas J.، نويسنده ,
Abstract :
Summary
e 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.
