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

Lisa Pirrie; Anna R. McCarthy; Louise L. Major; Vaida Morkunaite; Asta Zubriene; Daumantas Matulis; Sonia Lain; Tomas Lebl; Nicholas J. Westwood

doi:10.3390/molecules171012206

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

Lisa Pirrie, Anna R. McCarthy, Louise L. Major, Vaida Morkunaite, Asta Zubriene, Daumantas Matulis, Sonia Lain, Tomas Lebl, Nicholas J. Westwood

Research output: Contribution to journal › Article › peer-review

Abstract

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 H-1-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.

Original language	English
Pages (from-to)	12206-12224
Number of pages	19
Journal	Molecules
Volume	17
Issue number	10
DOIs	https://doi.org/10.3390/molecules171012206
Publication status	Published - Oct 2012

Keywords

Sirtuin
Chemical tool
Deacetylase assay
Neurodegenerative diseases

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10.3390/molecules171012206

Pirrie2012molecules 17 12206 v2
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
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Cite this

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

abstract = "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 H-1-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.",

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year = "2012",

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AU - Pirrie, Lisa

AU - McCarthy, Anna R.

AU - Major, Louise L.

AU - Morkunaite, Vaida

AU - Zubriene, Asta

AU - Matulis, Daumantas

AU - Lain, Sonia

AU - Lebl, Tomas

AU - Westwood, Nicholas J.

PY - 2012/10

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N2 - 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 H-1-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.

AB - 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 H-1-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.

KW - Sirtuin

KW - Chemical tool

KW - Deacetylase assay

KW - Neurodegenerative diseases

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

Abstract

Keywords

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CRUK Studentship PIRRIE: CRUK Core Studentship PIRRIE

ROYAL SOCIETY RESEARCH FELLOWSHIP: Chemical Genetic Approach

Cite this

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

CRUK Studentship PIRRIE: CRUK Core Studentship PIRRIE

ROYAL SOCIETY RESEARCH FELLOWSHIP: Chemical Genetic Approach

Cite this

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