Discovery of novel and selective SIRT6 inhibitors

Marco Daniele Parenti; Alessia Grozio; Inga Bauer; Lauretta Galeno; Patrizia Damonte; Enrico Millo; Giovanna Sociali; Claudio Franceschi; Alberto Ballestrero; Santina Bruzzone; Alberto Del Rio; Alessio Nencioni

doi:10.1021/jm500487d

Discovery of novel and selective SIRT6 inhibitors

Marco Daniele Parenti, Alessia Grozio, Inga Bauer, Lauretta Galeno, Patrizia Damonte, Enrico Millo, Giovanna Sociali, Claudio Franceschi, Alberto Ballestrero, Santina Bruzzone, Alberto Del Rio, Alessio Nencioni

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

Abstract

SIRT6 is an NAD⁺-dependent deacetylase with a role in the transcriptional control of metabolism and aging but also in genome stability and inflammation. Broad therapeutic applications are foreseen for SIRT6 inhibitors, including uses in diabetes, immune-mediated disorders, and cancer. Here we report on the identification of the first selective SIRT6 inhibitors by in silico screening. The most promising leads show micromolar IC₅₀s, have significant selectivity for SIRT6 versus SIRT1 and SIRT2, and are active in cells, as shown by increased acetylation at SIRT6 target lysines on histone 3, reduced TNF-α secretion, GLUT-1 upregulation, and increased glucose uptake. Taken together, these results show the value of these compounds as starting leads for the development of new SIRT6-targeting therapeutic agents.

Original language	English
Pages (from-to)	4796-4804
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	11
DOIs	https://doi.org/10.1021/jm500487d
Publication status	Published - Jun 12 2014

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Discovery of novel and selective SIRT6 inhibitors. / Parenti, Marco Daniele; Grozio, Alessia; Bauer, Inga; Galeno, Lauretta; Damonte, Patrizia; Millo, Enrico; Sociali, Giovanna; Franceschi, Claudio ; Ballestrero, Alberto; Bruzzone, Santina; Rio, Alberto Del; Nencioni, Alessio.

In: Journal of Medicinal Chemistry, Vol. 57, No. 11, 12.06.2014, p. 4796-4804.

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

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abstract = "SIRT6 is an NAD+-dependent deacetylase with a role in the transcriptional control of metabolism and aging but also in genome stability and inflammation. Broad therapeutic applications are foreseen for SIRT6 inhibitors, including uses in diabetes, immune-mediated disorders, and cancer. Here we report on the identification of the first selective SIRT6 inhibitors by in silico screening. The most promising leads show micromolar IC50s, have significant selectivity for SIRT6 versus SIRT1 and SIRT2, and are active in cells, as shown by increased acetylation at SIRT6 target lysines on histone 3, reduced TNF-α secretion, GLUT-1 upregulation, and increased glucose uptake. Taken together, these results show the value of these compounds as starting leads for the development of new SIRT6-targeting therapeutic agents.",

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AU - Parenti, Marco Daniele

AU - Grozio, Alessia

AU - Bauer, Inga

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AU - Damonte, Patrizia

AU - Millo, Enrico

AU - Sociali, Giovanna

AU - Franceschi, Claudio

AU - Ballestrero, Alberto

AU - Bruzzone, Santina

AU - Rio, Alberto Del

AU - Nencioni, Alessio

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AB - SIRT6 is an NAD+-dependent deacetylase with a role in the transcriptional control of metabolism and aging but also in genome stability and inflammation. Broad therapeutic applications are foreseen for SIRT6 inhibitors, including uses in diabetes, immune-mediated disorders, and cancer. Here we report on the identification of the first selective SIRT6 inhibitors by in silico screening. The most promising leads show micromolar IC50s, have significant selectivity for SIRT6 versus SIRT1 and SIRT2, and are active in cells, as shown by increased acetylation at SIRT6 target lysines on histone 3, reduced TNF-α secretion, GLUT-1 upregulation, and increased glucose uptake. Taken together, these results show the value of these compounds as starting leads for the development of new SIRT6-targeting therapeutic agents.

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