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

Sonia Lain, Jonathan J. Hollick, Johanna Campbell, Oliver D. Staples, Maureen Higgins, Mustapha Aoubala, Anna McCarthy, Virgina Appleyard, Karen E. Murray, Lee Baker, Alastair Thompson, Joanne Mathers, Stephen J. Holland, Michael J. R. Stark, Georgia Pass, Julie Woods, David P. Lane, Nicholas J. Westwood

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367 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)454-463
Number of pages10
JournalCancer Cell
Volume13
Issue number5
DOIs
Publication statusPublished - 6 May 2008

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    Lain, S., Hollick, J. J., Campbell, J., Staples, O. D., Higgins, M., Aoubala, M., McCarthy, A., Appleyard, V., Murray, K. E., Baker, L., Thompson, A., Mathers, J., Holland, S. J., Stark, M. J. R., Pass, G., Woods, J., Lane, D. P., & Westwood, N. J. (2008). Discovery, in vivo activity and mechanism of action of a small-molecule p53 activator. Cancer Cell, 13(5), 454-463. https://doi.org/10.1016/j.ccr.2008.03.004