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 journalArticle

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 languageEnglish
Pages (from-to)4796-4804
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number11
DOIs
Publication statusPublished - Jun 12 2014

Fingerprint

Genomic Instability
Immune System Diseases
Acetylation
Computer Simulation
NAD
Histones
Lysine
Up-Regulation
Inflammation
Glucose
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Parenti, M. D., Grozio, A., Bauer, I., Galeno, L., Damonte, P., Millo, E., ... Nencioni, A. (2014). Discovery of novel and selective SIRT6 inhibitors. Journal of Medicinal Chemistry, 57(11), 4796-4804. https://doi.org/10.1021/jm500487d

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 journalArticle

Parenti, MD, Grozio, A, Bauer, I, Galeno, L, Damonte, P, Millo, E, Sociali, G, Franceschi, C, Ballestrero, A, Bruzzone, S, Rio, AD & Nencioni, A 2014, 'Discovery of novel and selective SIRT6 inhibitors', Journal of Medicinal Chemistry, vol. 57, no. 11, pp. 4796-4804. https://doi.org/10.1021/jm500487d
Parenti MD, Grozio A, Bauer I, Galeno L, Damonte P, Millo E et al. Discovery of novel and selective SIRT6 inhibitors. Journal of Medicinal Chemistry. 2014 Jun 12;57(11):4796-4804. https://doi.org/10.1021/jm500487d
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. / Discovery of novel and selective SIRT6 inhibitors. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 11. pp. 4796-4804.
@article{7cca916cdb904363b066ae99b34d96ab,
title = "Discovery of novel and selective SIRT6 inhibitors",
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.",
author = "Parenti, {Marco Daniele} and Alessia Grozio and Inga Bauer and Lauretta Galeno and Patrizia Damonte and Enrico Millo and Giovanna Sociali and Claudio Franceschi and Alberto Ballestrero and Santina Bruzzone and Rio, {Alberto Del} and Alessio Nencioni",
year = "2014",
month = "6",
day = "12",
doi = "10.1021/jm500487d",
language = "English",
volume = "57",
pages = "4796--4804",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "11",

}

TY - JOUR

T1 - Discovery of novel and selective SIRT6 inhibitors

AU - Parenti, Marco Daniele

AU - Grozio, Alessia

AU - Bauer, Inga

AU - Galeno, Lauretta

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

PY - 2014/6/12

Y1 - 2014/6/12

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84902449175&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902449175&partnerID=8YFLogxK

U2 - 10.1021/jm500487d

DO - 10.1021/jm500487d

M3 - Article

C2 - 24785705

AN - SCOPUS:84902449175

VL - 57

SP - 4796

EP - 4804

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -