Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator

B136

A 30,000 compound library was screened using a p53-activation cell-based assay. To date, 2 hit compounds from this screen have proven activity in animal models. Here we focus on one of these hits, tenovin-1, along with its more water-soluble analogue, tenovin-6. Via a yeast genetic screen, biochemical assays and validation studies in mammalian cells we demonstrate that tenovins act through inhibition of the protein-deacetylase activities of SirT1 and SirT2 sirtuin family members. Tenovins are significantly more potent in mammalian cells than sirtuin inhibitors discovered using other approaches, decrease tumor growth in vivo as single agents and have led to the finding that wild-type and mutant p53 differ in their acetylation status. This study shows that using p53 as a sensor for compound activity in cells and exploiting the vast amount of available information on p53 regulation, rapidly leads to the discovery of small-molecule tools with potential as therapeutics.