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http://hdl.handle.net/10023/2845
| Title: | Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator |
| Authors: | Lain, Sonia
Hollick, Jonathan J.
Campbell, Johanna
Staples, Oliver D.
Higgins, Maureen
Aoubala, Mustapha
McCarthy, Anna
Appleyard, Virginia
Murray, Karen E.
Baker, Lee
Thompson, Alastair
Mathers, Joanne
Holland, Stephen J.
Stark, Michael J. R.
Pass, Georgia
Woods, Julie
Lane, David P.
Westwood, Nicholas J. |
| Keywords: | DNA-damage
Immunochemical analysis
Cell-survival
MDM2
Sirtuins
Deacetylases
Acetylation
Inhibitors
Enzymes
Disease
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
QR180 Immunology |
| Issue Date: | 6-May-2008 |
| Citation: | 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 , vol 13 , no. 5 , pp. 454-463 . |
| 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. |
| Version: | Postprint |
| Status: | Peer reviewed |
| URI: | http://hdl.handle.net/10023/2845
http://ukpmc.ac.uk/abstract/MED/18455128 |
| DOI: | http://dx.doi.org/10.1016/j.ccr.2008.03.004 |
| ISSN: | 1535-6108 |
| Type: | Journal article |
| Rights: | This is an electronic version of an open access article, published by Cell Press at http://dx.doi.org/10.1016/j.ccr.2008.03.004. Readers are permitted to read, download, print out, extract, reuse, archive, translate and distribute the article provided the appropriate credit is given to the authors and source of the work. |
| Appears in Collections: | University of St Andrews Research
Chemistry Research
Biomedical Sciences Research Complex (BSRC) Research
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