Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules

Angew Chem Int Ed Engl. 2017 Jan 19;56(4):1007-1011. doi: 10.1002/anie.201610082. Epub 2016 Dec 19.


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.

Keywords: deacetylases; drug discovery; enzymes; sirtuin activators; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrroles / chemistry
  • Pyrroles / metabolism*
  • Quinoxalines / chemistry
  • Quinoxalines / metabolism*
  • Sirtuins / chemistry
  • Sirtuins / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism*


  • Pyrroles
  • Quinoxalines
  • Small Molecule Libraries
  • pyrrolo(1,2-a)quinoxaline
  • SIRT6 protein, human
  • Sirtuins