Sirtuin-2 (Sirt2) ligands as inhibitors of lysine long-chain deacylation and chemical tools for protein degradation

Sirtuins是一种依赖于NAD的赖氨酸脱酰酶，它能从组蛋白和其他底物蛋白质中的赖氨酸中分离出乙酰基，但也能从赖氨酸中分离出长链酰基。这种翻译后修饰正在调节新陈代谢、细胞增殖和迁移等关键细胞过程。Sirtuin异型Sirtuin2(SIRT2)被认为是肿瘤、炎症和神经退行性变药物开发的靶点。对脱乙酰基和长链去乙酰基的双重抑制被认为是潜在的抗癌药物的高效药物。在以前的工作中，我们已经开发了有效的和选择性的SIRT2抑制剂的新的先导结构，具有这种双重抑制特性，并且比选择性乙酰化抑制剂更好地阻止癌细胞的迁移。此外，我们还发现了迄今为止史无前例的长链脱乙酰化选择性抑制剂。在这个项目中，我们想要优化双乙酰化/脱乙酰化和选择性脱乙酰化抑制剂的效力和细胞效能，以进一步剖析SIRT2不同的氨基水解酶活性的作用，并开发它们的治疗潜力。除了“经典的”基于占位的抑制剂外，我们还致力于开发新的针对嵌合体的蛋白水解酶(PROTACs)作为SIRT2的正交表。它们是同时结合SIRT2和合适的E3连接酶的杂交抑制剂。这导致SIRT2泛素化和随后的蛋白酶体降解，也将导致双重活性图谱。除了Cereblon和VHL等有效的连接酶外，我们还将为我们发现的适合SIRT2降解的连接酶Parkin开发新的配体，并将扩大SIRT2、PROTACs和PROTACs的可用武器库。

Sirtuins are NAD-dependent lysine deacylases that cleave off acetyl but also long chain acyl groups from lysines in histones and other substrate proteins. This posttranslational modification is regulating key cellular processes like metabolism, cell proliferation and migration. The Sirtuin isotype Sirtuin2 (Sirt2) has been postulated as a target for the development for drugs in oncology, inflammation and neurodegeneration. A dual inhibition of deacetylation and long chain deacylation has been postulated as highly effecive for potential anticancer drugs. In previous work we have developed new lead structures for potent and selective Sirt2 inhibitors that have this dual inhibition profile and block cancer cell migration better than selective acetylation inhibitors. In addition, we have discovered selective inhibitors for long chain deacylation which are unprecedented so far. In this project, we want to optimize potency and cellular efficacy of dual acetylation/deacylation and selective deacylation inhibitors to further dissect the role of the different amidohydrolase activities of Sirt2 and to exploit their therapeutic potential. Besides „classical“, occupancy based inhibitors we also aim at developing new Proteolysis targeting chimeras (PROTACs) for Sirt2 as an orthogonal apporach. that are hybrid inhibitors which simultaneously engage Sirt2 and a suitable E3 ligase. This leads to Sirt2 ubiquitylation and subsequent proteasomal degradation and will also result in a dual activity profile. Besides validated ligases like Cereblon and VHL we will develop new ligands for the ligase Parkin which we had discovered to be suitable for Sirt2 degradation and will expand the available arsenal for Sirt2 PROTACs and PROTACs in general.