2-(Methyl(phenyl)amino)-N-(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-06-12 DOI:10.1002/ddr.22224

Selen Gozde Kaya, Gokcen Eren, Alberto Massarotti, Filiz Bakar-Ates, Erva Ozkan, Mahmut Gozelle, Yesim Ozkan

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Abstract

The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD⁺-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC₅₀ values of 9.97, 5.74, and 8.92 μM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.

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2-(甲基(苯基)氨基)-N-(苯氧基苯基)乙酰胺结构基团代表选择性抑制 SIRT2 的框架。

哺乳动物细胞质蛋白 SIRT2 是组蛋白去乙酰化酶家族的第三类成员，具有依赖 NAD+ 的赖氨酸去乙酰化酶/去乙酰化酶活性。SIRT2 的失调与多种疾病的发病机制有关，包括神经系统疾病、代谢性疾病和癌症；因此，SIRT2 成为一个潜在的治疗靶点。在此，我们通过对新发现的 STH2 进行结构优化，发现了一系列二芳基乙酰胺类化合物（ST61-ST90），从而增强了 SIRT2 的抑制效力和选择性。其中，ST72、ST85 和 ST88 能选择性地抑制 SIRT2，IC50 值分别为 9.97、5.74 和 8.92 μM。最后，整个研究还对对接化合物的结合模式和 SIRT2 配体复合物的稳定性进行了硅学预测。我们希望我们的研究结果能为设计SIRT2的选择性抑制剂提供大量信息。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.