Nielsen Alexander L, Rajabi Nima, Kudo Norio, Lundø Kathrine, Moreno-Yruela Carlos, Bæk Michael, Fontenas Martin, Lucidi Alessia, Madsen Andreas S, Yoshida Minoru, Olsen Christian A
Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen Universitetsparken 2 DK-2100 Copenhagen Denmark
RIKEN Center for Sustainable Resource Science (S13) Hirosawa 2-1 Wako Saitama 351-0198 Japan.
RSC Chem Biol. 2021 Jan 14;2(2):612-626. doi: 10.1039/d0cb00036a. eCollection 2021 Apr 1.
Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of chemical probes that are potent, selective, stable in serum, water-soluble, and inhibit SIRT2-mediated deacetylation and demyristoylation in cells. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics.
沉默调节蛋白2（SIRT2）是一种蛋白质脱酰基酶，可从翻译后修饰的赖氨酸残基上去除乙酰基和长链酰基。它影响细胞中的多种生物学功能，并且在神经退行性疾病和癌症方面均被视为药物靶点。因此，获得特征明确且稳定的工具化合物对于持续研究该酶的复杂功能至关重要。在此，我们报告了一系列化学探针，这些探针具有强效、选择性、在血清中稳定、水溶性好的特点，并且能够抑制细胞中SIRT2介导的去乙酰化和去肉豆蔻酰化。与目前的SIRT2抑制剂情况相比，这是单个化合物中所具备的独特特征组合。我们期望所开发的化学类型能够在研究健康细胞和患病细胞中SIRT2功能方面得到广泛应用，并为未来治疗药物的开发提供基础。
