The NAD⁺-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from Schistosoma mansoni (SmSirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the “Kinetobox” library as a dual inhibitor of human Sirt2 (hSirt2) and SmSirt2. Herein, we describe the structure–activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.

中文翻译：

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1,2,4-恶二唑抑制 NAD+ 依赖性赖氨酸脱酰酶 Sirtuin 2 的结构-活性研究


NAD ⁺ 依赖性赖氨酸脱酰酶 Sirtuin 2 (Sirt2) 参与多种病理状况，例如癌症。因此，针对 Sirt2 的治疗目的越来越受到人们的关注。此外，曼氏血吸虫 (Schistosoma mansoni) 的直系同源物 (SmSirt2) 已被认为可用于治疗被忽视的热带病血吸虫病。我们之前从“Kinetobox”库的筛选中鉴定出一种基于 1,2,4-恶二唑的支架作为人 Sirt2 (hSirt2) 和 SmSirt2 的双重抑制剂。在此，我们描述了基于 1,2,4-恶二唑的类似物的结构-活性研究，这些类似物是人类 Sirt2 脱乙酰化的有效抑制剂。正如对接研究所提出的，底物竞争性和辅因子非竞争性结合抑制模式可以通过结合测定和动力学分析在体外确定，并通过与 hSirt2 复合的恶二唑抑制剂的晶体结构进一步证实。优化的类似物可降低细胞活力并抑制前列腺癌细胞迁移，与体外和细胞内的 Sirt2 脱乙酰酶抑制相关。