Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator.
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.
Lain
Sonia
S
Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK. s.lain@dundee.ac.uk
Hollick
Jonathan J
JJ
Campbell
Johanna
J
Staples
Oliver D
OD
Higgins
Maureen
M
Aoubala
Mustapha
M
McCarthy
Anna
A
Appleyard
Virginia
V
Murray
Karen E
KE
Baker
Lee
L
Thompson
Alastair
A
Mathers
Joanne
J
Holland
Stephen J
SJ
Stark
Michael J R
MJ
Pass
Georgia
G
Woods
Julie
J
Lane
David P
DP
Westwood
Nicholas J
NJ
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*
D019063:Tenascin; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins