Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration

IF 4.9 Q1 CHEMISTRY, MEDICINAL

ACS Pharmacology and Translational Science Pub Date : 2024-07-17 DOI:10.1021/acsptsci.4c0028210.1021/acsptsci.4c00282

Chandra Choudhury, James E. Egleton, Neville J. Butcher, Angela J. Russell and Rodney F. Minchin*,

{"title":"Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration","authors":"Chandra Choudhury, James E. Egleton, Neville J. Butcher, Angela J. Russell and Rodney F. Minchin*, ","doi":"10.1021/acsptsci.4c0028210.1021/acsptsci.4c00282","DOIUrl":null,"url":null,"abstract":"<p >Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both <i>in vitro</i> and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 8","pages":"2326–2332 2326–2332"},"PeriodicalIF":4.9000,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Pharmacology and Translational Science","FirstCategoryId":"1085","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsptsci.4c00282","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.

Abstract Image

查看原文本刊更多论文

芳香胺 N-乙酰转移酶 1 的小分子抑制剂可减轻细胞呼吸作用

研究表明，芳胺 N-乙酰转移酶 1（NAT1）的表达会削弱线粒体的功能，这表明它是治疗线粒体功能障碍疾病的一个很有前景的药物靶点。本文研究了几种作为 NAT1 小分子抑制剂的第二代萘醌类化合物。结果表明，这些化合物在体外和全细胞中都有抑制作用。我们进一步研究了一种先导化合物（Cmp350）改变 MDA-MB-231 细胞线粒体代谢的能力。在抑制 NAT1 的浓度超过 85% 时，没有观察到明显的毒性。此外，抑制剂还能降低基础呼吸和储备呼吸能力，而不影响 ATP 的产生。用 Cmp350 处理的细胞几乎完全依赖葡萄糖作为燃料来源。我们推测，Cmp350 是开发 NAT1 靶向抑制剂的极佳先导化合物，既可作为实验工具，也可作为治疗肌萎缩性脊髓侧索硬化症、癌症恶病质和败血症等高代谢疾病的疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

期刊介绍： ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.