Discovery and Validation of SIRT2 Inhibitors Based on Tenovin-6: Use of a 1H-NMR Method to Assess Deacetylase Activity

Molecules

Lisa Pirrie³  Anna R. McCarthy³  Louise L. Major³  Vaida Morkūnaitė¹  Asta Zubrienė¹  Daumantas Matulis¹  Sonia Lain²  Tomas Lebl³ 

[1] Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graiciuno 8LT-02241, Vilnius, Lithuania;Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden;School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews and EaStCHEM, North Haugh, St Andrews, Fife KY16 9ST, UK

关键词: sirtuin;    chemical tool;    deacetylase assay;    neurodegenerative diseases;   

DOI  :  10.3390/molecules171012206

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.