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

Sirtuins是NAD依赖性赖氨酸脱酰酶，其从组蛋白和其他底物蛋白中的赖氨酸上切割乙酰基以及长链酰基。这种翻译后修饰调节关键的细胞过程，如代谢，细胞增殖和迁移。Sirtuin同种型Sirtuin 2（Sirt 2）已被假定为肿瘤学、炎症和神经变性药物开发的靶标。对脱乙酰基和长链脱乙酰基的双重抑制被认为是潜在抗癌药物的高效抑制剂。在以前的工作中，我们已经开发了新的先导结构，用于有效和选择性的Sirt 2抑制剂，其具有这种双重抑制作用，并且比选择性乙酰化抑制剂更好地阻断癌细胞迁移。此外，我们还发现了迄今为止前所未有的长链脱酰化的选择性抑制剂。在这个项目中，我们希望优化双重乙酰化/脱酰化和选择性脱酰化抑制剂的效力和细胞功效，以进一步剖析Sirt 2的不同酰胺水解酶活性的作用，并开发其治疗潜力。除了“经典的”基于占据的抑制剂之外，我们还旨在开发针对Sirt 2的新的蛋白水解靶向嵌合体（PROTAC）作为正交方法。它们是同时接合Sirt 2和合适的E3连接酶的杂合抑制剂。这导致Sirt 2泛素化和随后的蛋白酶体降解，也将导致双重活性谱。除了经过验证的连接酶（如Cereblon和VHL）外，我们还将为我们发现适合Sirt 2降解的连接酶Parkin开发新的配体，并将扩大Sirt 2 PROTAC和PROTAC的可用库。

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.