Journal of Biological Chemistry
Volume 276, Issue 42, 19 October 2001, Pages 38837-38843
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GENES: STRUCTURE AND REGULATION
Identification of a Class of Small Molecule Inhibitors of the Sirtuin Family of NAD-dependent Deacetylases by Phenotypic Screening*

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The yeast transcriptional repressor Sir2p silences gene expression from the telomeric, rDNA, and silent mating-type loci and may play a role in higher order processes such as aging. Sir2p is the founding member of a large family of NAD-dependent deacetylase enzymes, named the sirtuins. These proteins are conserved from prokaryotes to eukaryotes, but most remain uncharacterized, including all seven human sirtuins. A reverse chemical genetic approach would be useful in identifying the biological function of sirtuins in a wide variety of experimental systems, but no cell-permeable small molecule inhibitors of sirtuins have been reported previously. Herein we describe a high throughput, phenotypic screen in cells that led to the discovery of a class of sirtuin inhibitors. All three compounds inhibited yeast Sir2p transcriptional silencing activity in vivo, and yeast Sir2p and human SIRT2 deacetylase activity in vitro. Such specific results demonstrate the utility and robustness of this screening methodology. Structure-activity relationship analysis of the compounds identified a key hydroxy-napthaldehyde moiety that is necessary and sufficient for inhibitory activity. Preliminary studies using one of these compounds suggest that inhibition of sirtuins interferes with body axis formation in Arabidopsis.

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Published, JBC Papers in Press, August 1, 2001, DOI 10.1074/jbc.M106779200

*

This work was supported in part by NIGMS, National Institutes of Health Grant GM38627 (to S. L. S.). Research at the Harvard Institute of Chemistry and Chemical Biology is supported by the NCI, the Keck Foundation, Merck KGOA and Merck & Co. S. L. S. is an Investigator at the Howard Hughes Medical Institute. H. E. B. is supported by a post-doctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research (sponsored by Merck & Co.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.