Schiedel Matthias, Rumpf Tobias, Karaman Berin, Lehotzky Attila, Oláh Judit, Gerhardt Stefan, Ovádi Judit, Sippl Wolfgang, Einsle Oliver, Jung Manfred
Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg , Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
J Med Chem. 2016 Feb 25;59(4):1599-612. doi: 10.1021/acs.jmedchem.5b01517. Epub 2016 Jan 7.
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.
沉默调节蛋白是依赖烟酰胺腺嘌呤二核苷酸（NAD⁺）的蛋白质去酰基酶，可从组蛋白和其他底物蛋白中赖氨酸的ε-氨基上切除乙酰基以及其他酰基。人类沉默调节蛋白2（hSirt2）活性失调与癌症、炎症和神经退行性疾病的发病机制有关，这使得调节hSirt2活性成为药物干预的一个有前景的策略。我们最近发现了沉默调节蛋白重排配体（SirReals）作为高效且具有同型选择性的hSirt2抑制剂。在此，我们进行了一项明确的构效关系研究，该研究阐明了SirReals的独特特征，并探究了在该支架上进行修饰对抑制剂效力的限制。此外，我们展示了hSirt2与一种优化的SirReal衍生物形成复合物的晶体结构，该衍生物表现出改善的体外活性。最后，我们展示了由我们优化的先导结构导致的hSirt2靶向微管蛋白的细胞高乙酰化。
