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

doi:10.1016/j.ccr.2008.03.004

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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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 language	English
Pages (from-to)	454-463
Number of pages	10
Journal	Cancer Cell
Volume	13
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2008.03.004
Publication status	Published - 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

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

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.",

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

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Lain, S, Hollick, JJ, Campbell, J, Staples, OD, Higgins, M, Aoubala, M, McCarthy, A, Appleyard, V, Murray, KE, Baker, L, Thompson, A, Mathers, J, Holland, SJ, Stark, MJR, Pass, G, Woods, J, Lane, DP & Westwood, NJ 2008, 'Discovery, in vivo activity and mechanism of action of a small-molecule p53 activator', Cancer Cell, vol. 13, no. 5, pp. 454-463. https://doi.org/10.1016/j.ccr.2008.03.004

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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.

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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.

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VL - 13

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JO - Cancer Cell

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

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