Discovery of novel and selective SIRT6 inhibitors.
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.
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum, University of Bologna , Via S. Giacomo 14, 40126 Bologna, Italy.
Marco Daniele
MD
Parenti
Alessia
A
Grozio
Inga
I
Bauer
Lauretta
L
Galeno
Patrizia
P
Damonte
Enrico
E
Millo
Giovanna
G
Sociali
Claudio
C
Franceschi
Alberto
A
Ballestrero
Santina
S
Bruzzone
Alberto
A
Del Rio
Alessio
A
Nencioni
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D005663:Furans; D051272:Glucose Transporter Type 1; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D012459:Salicylates; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C516592:SIRT6 protein, human; D037761:Sirtuins; D005947:Glucose