Discovery of Novel and Selective SIRT6 Inhibitors

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

来源：Journal of Medicinal Chemistry, 2014, 57(11): 4796-4804.

DOI：10.1021/jm500487d

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 IC(50)s, 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-alpha 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.

• 出版日期2014-6-12