Discovery of Novel and Selective SIRT6 Inhibitors

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4796-4804
• 全文大小：513K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

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-伪 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.