Discovery and validation of SIRT2 inhibitors based on tenovin-6: use of a ¹H-NMR method to assess deacetylase activity

• Published in: Molecules (Basel, Switzerland) Switzerland), 2012-10, Vol.17 (10), p.12206-12224
• Main Authors: Pirrie, Lisa, McCarthy, Anna R, Major, Louise L, Morkūnaitė, Vaida, Zubrienė, Asta, Matulis, Daumantas, Lain, Sonia, Lebl, Tomas, Westwood, Nicholas J
• Format: Article
• Language: English
• Subjects: Acetylation; Acids; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; chemical tool; deacetylase assay; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Histones - metabolism; Humans; Kinases; Medicin och hälsovetenskap; neurodegenerative diseases; Nuclear Magnetic Resonance, Biomolecular; Peptides; Reproducibility of Results; sirtuin; Sirtuin 2 - antagonists & inhibitors; Sirtuin 2 - metabolism; Stem cells
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules171012206

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.