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Adenosine Mimetics as Inhibitors of NAD⁺-Dependent Histone Deacetylases, from Kinase to Sirtuin Inhibition

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Johannes Trapp,^† Anne Jochum,^‡ Rene Meier,^§ Laura Saunders, Brett Marshall, Conrad Kunick, Eric Verdin, Peter Goekjian,^‡ Wolfgang Sippl,^§ and Manfred Jung^†*

Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universitt Freiburg, Albertstrasse 25, 79104 Freiburg, Germany, LCO2-Glycochimie, UMR 5181 Mthodologie de Synthse et Molcules Bioactives, Universit Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France, Department of Pharmaceutical Chemistry, Martin-Luther Universitt Halle-Wittenberg, Wolfgang-Langenbeckstrasse 4, 06120 Halle/Saale, Germany, Gladstone Institute of Virology and Immunology, University of California, 1650 Owens Street, San Francisco, California 94158, and Institut fr Pharmazeutische Chemie, Technische Universitt Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany

J. Med. Chem., 2006, 49 (25), pp 7307–7316

DOI: 10.1021/jm060118b

Publication Date (Web): November 10, 2006

†

Albert-Ludwigs-Universität Freiburg.

‡

Université Claude Bernard Lyon 1.

Martin-Luther Universität Halle-Wittenberg.

University of California.

Technische Universität Braunschweig.

To whom correspondence should be addressed. E-mail: manfred.jung@ pharmazie.uni-freiburg.de; Tel: +49-761-203-4896; Fax: +49-761-203-6321.

Abstract

NAD⁺-dependent histone deacetylases, sirtuins, cleave acetyl groups from lysines of histones and other proteins to regulate their activity. Identification of potent selective inhibitors would help to elucidate sirtuin biology and could lead to useful therapeutic agents. NAD⁺ has an adenosine moiety that is also present in the kinase cofactor ATP. Kinase inhibitors based upon adenosine mimesis may thus also target NAD⁺-dependent enzymes. We present a systematic approach using adenosine mimics from one cofactor class (kinase inhibitors) as a viable method to generate new lead structures in another cofactor class (sirtuin inhibitors). Our findings have broad implications for medicinal chemistry and specifically for sirtuin inhibitor design. Our results also raise a question as to whether selectivity profiling for kinase inhibitors should be limited to ATP-dependent targets.

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Published In Issue December 14, 2006
Received February 3, 2006

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Article

Adenosine Mimetics as Inhibitors of NAD⁺-Dependent Histone Deacetylases, from Kinase to Sirtuin Inhibition