TY - JOUR
T1 - Discovery, in vivo activity and mechanism of action of a small-molecule p53 activator
AU - Lain, Sonia
AU - Hollick, Jonathan J.
AU - Campbell, Johanna
AU - Staples, Oliver D.
AU - Higgins, Maureen
AU - Aoubala, Mustapha
AU - McCarthy, Anna
AU - Appleyard, Virgina
AU - Murray, Karen E.
AU - Baker, Lee
AU - Thompson, Alastair
AU - Mathers, Joanne
AU - Holland, Stephen J.
AU - Stark, Michael J. R.
AU - Pass, Georgia
AU - Woods, Julie
AU - Lane, David P.
AU - Westwood, Nicholas J.
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2008/5/6
Y1 - 2008/5/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=42949114938&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2008.03.004
DO - 10.1016/j.ccr.2008.03.004
M3 - Article
C2 - 18455128
AN - SCOPUS:42949114938
SN - 1535-6108
VL - 13
SP - 454
EP - 463
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -