Choudhury Chandra, Egleton James E, Butcher Neville J, Russell Angela J, Minchin Rodney F
School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, 4069 Queensland Australia.
Department of Chemistry, University of Oxford, 12A Mansfield Road, Oxford OX1 3TA, U.K.
ACS Pharmacol Transl Sci. 2024 Jul 17;7(8):2326-2332. doi: 10.1021/acsptsci.4c00282. eCollection 2024 Aug 9.
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 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.
芳胺N - 乙酰基转移酶1（NAT1）的表达已被证明会削弱线粒体功能，这表明它是线粒体功能障碍疾病中一个有前景的药物靶点。在此，研究了几种第二代萘醌作为NAT1的小分子抑制剂。结果表明，这些化合物在体外和全细胞中均有抑制作用。对一种先导化合物（Cmp350）改变MDA - MB - 231细胞中线粒体代谢的能力进行了进一步研究。在抑制NAT1超过85%的浓度下，未观察到明显毒性。此外，该抑制剂降低了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靶向抑制剂的优秀先导化合物，可作为实验工具以及治疗诸如肌萎缩侧索硬化、癌症恶病质和败血症等高代谢疾病的药物。
