Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Department of Clinical Biochemistry, School of Laboratory Medicine, Chengdu Medical College, Chengdu 610050, China; Department of Respiratory Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610050, China.
Eur J Pharm Sci. 2019 Sep 1;137:105010. doi: 10.1016/j.ejps.2019.105010. Epub 2019 Jul 17.
Acetyl-coA carboxylase 1 (ACC1) is the first and rate-limiting enzyme in the de novo fatty acid synthesis (FASyn) pathway. In this study, through public database analysis and clinic sample test, we for the first time verified that ACC1 mRNA is overexpressed in non-small-cell lung cancer (NSCLC), which is accompanied by reduced DNA methylation at CpG island S shore of ACC1. Our study further demonstrated that higher ACC1 levels are associated with poor prognosis in NSCLC patients. Besides, we developed a novel synthetic route for preparation of a known ACC inhibitor ND-646, synthesized a series of its derivatives and evaluated their activity against the enzyme ACC1 and the A549 cell. As results, most of the tested compounds showed potent ACC1 inhibitory activity with IC values 3-10 nM. Among them, compounds A2, A7 and A9 displayed strong cancer inhibitory activity with IC values 9-17 nM by impairing cell growth and inducing cell death. Preliminary SAR analysis clearly suggested that (R)-configuration and amide group were vital to ACC1 and A549 inhibition, since compound (S)-A1 (the enantiomer of ND-646) had poor activity of ACC1 inhibition and the carboxylic acid ND-630 almost lost anticancer effect on A549 cells. Collectively, these findings indicate that ACC1 is a potential biomarker and target for non-small-cell lung cancer, and ND-646 and its derivatives as ACC1 inhibitors deserve further study for treatment of NSCLC.
乙酰辅酶 A 羧化酶 1（ACC1）是从头脂肪酸合成（FASyn）途径中的第一个限速酶。在这项研究中，通过公共数据库分析和临床样本测试，我们首次验证了 ACC1mRNA 在非小细胞肺癌（NSCLC）中过表达，同时伴随着 ACC1 的 CpG 岛 S 岸 DNA 甲基化减少。我们的研究进一步表明，ACC1 水平较高与 NSCLC 患者的预后不良相关。此外，我们开发了一种新的 ACC 抑制剂 ND-646 的合成路线，合成了一系列衍生物，并评估了它们对酶 ACC1 和 A549 细胞的活性。结果表明，大多数测试化合物对 ACC1 具有很强的抑制活性，IC 值为 3-10nM。其中，化合物 A2、A7 和 A9 通过抑制细胞生长和诱导细胞死亡，对 ACC1 和 A549 具有很强的抑制活性，IC 值为 9-17nM。初步的 SAR 分析清楚地表明，（R）构型和酰胺基对 ACC1 和 A549 的抑制至关重要，因为化合物（S）-A1（ND-646 的对映异构体）对 ACC1 抑制活性差，羧酸 ND-630 对 A549 细胞几乎失去了抗癌作用。总之，这些发现表明 ACC1 是潜在的非小细胞肺癌生物标志物和靶点，ND-646 及其衍生物作为 ACC1 抑制剂值得进一步研究用于治疗 NSCLC。
