Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 4, Pages 1007-1011Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201610082
Keywords
deacetylases; drug discovery; enzymes; sirtuin activators; structural biology
Categories
Funding
- DFG [1701/15-1]
- Oberfrankenstiftung
- PRIN [2012CTAYSY]
- AIRC-TRIDEO [17515]
- NIH [R01AG050997]
- U.S. Department of Veterans Affairs (Merit Review)
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Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.
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