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

被引：423

作者：

Lain, Sonia ^{[1
]}

Hollick, Jonathan J. ^{[4
,5
]}

Campbell, Johanna ^{[1
]}

Staples, Oliver D. ^{[1
]}

Higgins, Maureen ^{[1
]}

Aoubala, Mustapha ^{[1
]}

McCarthy, Anna ^{[1
,4
,5
]}

Appleyard, Virginia ^{[1
]}

Murray, Karen E. ^{[1
]}

Baker, Lee ^{[1
]}

Thompson, Alastair ^{[1
]}

Mathers, Joanne ^{[1
]}

Holland, Stephen J. ^{[6
]}

Stark, Michael J. R. ^{[6
]}

Pass, Georgia ^{[2
]}

Woods, Julie ^{[3
]}

Lane, David P. ^{[7
]}

Westwood, Nicholas J. ^{[4
,5
]}

机构：

[1] Univ Dundee, Dept Surg & Mol Oncol, Dundee DD1 9SY, Scotland

[2] Univ Dundee, Canc Res UK Mol Pharmacol Unit, Dundee DD1 9SY, Scotland

[3] Univ Dundee, Ninewells Hosp & Med Sch, Dept Dermatol, Dundee DD1 9SY, Scotland

[4] Univ St Andrews, Sch Chem, St Andrews KY16 9ST, Fife, Scotland

[5] Univ St Andrews, Ctr Biomol Sci, St Andrews KY16 9ST, Fife, Scotland

[6] Univ Dundee, Coll Life Sci, Wellcome Trust Ctr Gene Regulat & Express, Dundee DD1 5EH, Scotland

[7] Inst Mol & Cell Biol, Dept Cell Cycle Control, Singapore 138673, Singapore

来源：

CANCER CELL | 2008年 / 13卷 / 05期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1016/j.ccr.2008.03.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：454 / 463

页数：10

共 52 条

[1] Post-translational modifications and activation of p53 by genotoxic stresses [J].

Appella, E ;

Anderson, CW .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (10) :2764-2772

[2] IMMUNOCHEMICAL ANALYSIS OF THE P53 ONCOPROTEIN IN MATCHED PRIMARY AND METASTATIC HUMAN TUMORS [J].

BARTKOVA, J ;

BARTEK, J ;

VOJTESEK, B ;

LUKAS, J ;

REJTHAR, A ;

KOVARIK, J ;

MILLIS, RR ;

LANE, DP ;

BARNES, DM .

EUROPEAN JOURNAL OF CANCER, 1993, 29A (06) :881-886

[3] Identification of a small molecule inhibitor of Sir2p [J].

Bedalov, A ;

Gatbonton, T ;

Irvine, WP ;

Gottschling, DE ;

Simon, JA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (26) :15113-15118

[4] Pilot screening programme for small molecule activators of p53 [J].

Berkson, RG ;

Hollick, JJ ;

Westwood, NJ ;

Woods, JA ;

Lane, DP ;

Lain, S .

INTERNATIONAL JOURNAL OF CANCER, 2005, 115 (05) :701-710

[5] DNA damage triggers DRB-resistant phosphorylation of human p53 at the CK2 site [J].

Blaydes, JP ;

Hupp, TR .

ONCOGENE, 1998, 17 (08) :1045-1052

[6] Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases [J].

Borra, MT ;

Langer, MR ;

Slama, JT ;

Denu, JM .

BIOCHEMISTRY, 2004, 43 (30) :9877-9887

[7] Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice [J].

Cheng, HL ;

Mostoslavsky, R ;

Saito, S ;

Manis, JP ;

Gu, YS ;

Patel, P ;

Bronson, R ;

Appella, E ;

Alt, FW ;

Chua, KF .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (19) :10794-10799

[8] Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress [J].

Chua, KF ;

Mostoslavsky, R ;

Lombard, DB ;

Pang, WW ;

Saito, S ;

Franco, S ;

Kaushal, D ;

Cheng, HL ;

Fischer, MR ;

Stokes, N ;

Murphy, MM ;

Appella, E ;

Alt, FW .

CELL METABOLISM, 2005, 2 (01) :67-76

[9]

Cuperus G, 2002, GENETICS, V162, P633

[10] Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival [J].

Ford, J ;

Jiang, M ;

Milner, J .

CANCER RESEARCH, 2005, 65 (22) :10457-10463

← 1 2 3 4 5 6 →