Discovery of Potent and Selective Sirtuin 2 (SIRT2) Inhibitors Using a Fragment-Based Approach
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- 作者：Huaqing Cui ; Zeeshan Kamal ; Teng Ai ; Yanli Xu ; Swati S. More ; Daniel J. Wilson ; Liqiang Chen
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：October 23, 2014
- 年：2014
- 卷：57
- 期：20
- 页码：8340-8357
- 全文大小：749K
- ISSN：1520-4804
文摘
Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD+-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene鈥揵enzamides and 鈭抧icotinamides. Biochemical evaluation of these two series provided structure鈥揳ctivity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of 伪-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD+. Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.