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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...

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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
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cited_by cdi_FETCH-LOGICAL-c4576-24785d2fc0aec2b7fa65d014c5315f17b3e0eabfb097592c50244d5d1e204dc33
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container_title Molecules (Basel, Switzerland)
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creator Pirrie, Lisa
McCarthy, Anna R
Major, Louise L
Morkūnaitė, Vaida
Zubrienė, Asta
Matulis, Daumantas
Lain, Sonia
Lebl, Tomas
Westwood, Nicholas J
description 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.
doi_str_mv 10.3390/molecules171012206
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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
title Discovery and validation of SIRT2 inhibitors based on tenovin-6: use of a ¹H-NMR method to assess deacetylase activity
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