Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure–Activity Relationship Study
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- 作者：Matthias Schiedel ; Tobias Rumpf ; Berin Karaman ; Attila Lehotzky ; Judit Oláh ; Stefan Gerhardt ; Judit Ovádi ; Wolfgang Sippl ; Oliver Einsle ; Manfred Jung
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：February 25, 2016
- 年：2016
- 卷：59
- 期：4
- 页码：1599-1612
- 全文大小：760K
- ISSN：1520-4804
文摘
Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure–activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.