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 | |
| Publication status | Published - Jun 12 2014 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
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
}
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.
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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 -