Discovery and validation of SIRT2 inhibitors based on tenovin-6: use of a ¹H-NMR method to assess deacetylase activity.
The search for potent and selective sirtuin inhibitors continues as chemical tools of this type are of use in helping to assign the function of this interesting class of deacetylases. Here we describe SAR studies starting from the unselective sirtuin inhibitor tenovin-6. These studies identify a sub-micromolar inhibitor that has increased selectivity for SIRT2 over SIRT1 compared to tenovin-6. In addition, a ¹H-NMR-based method is developed and used to validate further this class of sirtuin inhibitors. A thermal shift analysis of SIRT2 in the presence of tenovin-6, -43, a control tenovin and the known SIRT2 inhibitor AGK2 is also presented.
School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, North Haugh, St Andrews, Fife KY16 9ST, UK.
Lisa
L
Pirrie
Anna R
AR
McCarthy
Louise L
LL
Major
Vaida
V
Morkūnaitė
Asta
A
Zubrienė
Daumantas
D
Matulis
Sonia
S
Lain
Tomas
T
Lebl
Nicholas J
NJ
Westwood
D000107:Acetylation; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D015203:Reproducibility of Results; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; D006657:Histones; C574854:tenovin-6; D056565:Sirtuin 2