Vogelmann A, Schiedel M, Wössner N, Merz A, Herp D, Hammelmann S, Colcerasa A, Komaniecki G, Hong J Y, Sum M, Metzger E, Neuwirt E, Zhang L, Einsle O, Groß O, Schüle R, Lin H, Sippl W, Jung M
Institute of Pharmaceutical Sciences, University of Freiburg Albertstraße 25 79104 Freiburg Germany
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg Nikolaus-Fiebiger-Straße 10 91058 Erlangen Germany.
RSC Chem Biol. 2022 Mar 1;3(4):468-485. doi: 10.1039/d1cb00244a. eCollection 2022 Apr 6.
Sirtuin2 (Sirt2) with its NAD-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affinity Sirt2 selective Sirtuin-Rearranging Ligands (SirReals) that inhibit both Sirt2-dependent deacetylation and defatty-acylation and in cells. We show that simultaneous inhibition of both Sirt2 activities results in strongly reduced levels of the oncoprotein c-Myc and an inhibition of cancer cell migration. Furthermore, we describe the development of a NanoBRET-based assay for Sirt2, thereby providing a method to study cellular target engagement for Sirt2 in a straightforward and accurately quantifiable manner. Applying this assay, we could confirm cellular Sirt2 binding of our new Sirt2 inhibitors and correlate their anticancer effects with their cellular target engagement.
沉默调节蛋白2（Sirt2）及其依赖烟酰胺腺嘌呤二核苷酸（NAD）的去乙酰化酶和去脂肪酰化酶活性在特定细胞功能的调节中起着核心作用。Sirt2活性失调与许多疾病的发病机制相关，因此使Sirt2成为药物干预的一个有前景的靶点。在此，我们展示了新型高亲和力的Sirt2选择性沉默调节蛋白重排配体（SirReals），它们在细胞中抑制Sirt2依赖性去乙酰化和去脂肪酰化。我们表明，同时抑制Sirt2的两种活性会导致癌蛋白c-Myc水平大幅降低，并抑制癌细胞迁移。此外，我们描述了一种基于纳米生物发光共振能量转移（NanoBRET）的Sirt2检测方法的开发，从而提供了一种以直接且可准确量化的方式研究Sirt2细胞靶点结合的方法。应用该检测方法，我们能够确认新型Sirt2抑制剂与细胞Sirt2的结合，并将它们的抗癌效果与其细胞靶点结合情况相关联。
