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; Virginia 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, Virginia 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

Research output: Contribution to journal › Article › peer-review

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

DNA-damage
Immunochemical analysis
Cell-survival
MDM2
Sirtuins
Deacetylases
Acetylation
Inhibitors
Enzymes
Disease

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10.1016/j.ccr.2008.03.004

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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.",

keywords = "DNA-damage, Immunochemical analysis, Cell-survival, MDM2, Sirtuins, Deacetylases, Acetylation, Inhibitors, Enzymes, Disease",

author = "Sonia Lain and Hollick, \{Jonathan J.\} and Johanna Campbell and Staples, \{Oliver D.\} and Maureen Higgins and Mustapha Aoubala and Anna McCarthy and Virginia 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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doi = "10.1016/j.ccr.2008.03.004",

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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 - Lain, Sonia

AU - Hollick, Jonathan J.

AU - Campbell, Johanna

AU - Staples, Oliver D.

AU - Higgins, Maureen

AU - Aoubala, Mustapha

AU - McCarthy, Anna

AU - Appleyard, Virginia

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.

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.

KW - DNA-damage

KW - Immunochemical analysis

KW - Cell-survival

KW - MDM2

KW - Sirtuins

KW - Deacetylases

KW - Acetylation

KW - Inhibitors

KW - Enzymes

KW - Disease

UR - https://www.scopus.com/pages/publications/42949114938

UR - http://ukpmc.ac.uk/abstract/MED/18455128

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DO - 10.1016/j.ccr.2008.03.004

M3 - Article

SN - 1535-6108

VL - 13

SP - 454

EP - 463

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

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Keywords

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