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Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia

文献类型：期刊论文

作者Xie, Zhifu4; Zhang, Mei4; Song, Qian3,4; Cheng, Long3,4; Zhang, Xinwen4; Song, Gaolei3,4; Sun, Xinyu4; Gu, Min4; Zhou, Chendong4; Zhang, Yangming2,4
刊名ACTA PHARMACEUTICA SINICA B
出版日期2023-02-01
卷号13期号:2页码:739-753
关键词Hypercholesterolemia Atherosclerosis Liver ATP-Citrate lyase (ACLY) Lipogenesis Cholesterol efflux ACLY inhibitor
DOI10.1016/j.apsb.2022.06.011
文献子类Article
英文摘要Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC50 Z 5.31 + 1.2 mmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, ex-hibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treat-ment of hypercholesterolemia. 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词ATP-CITRATE LYASE ; DENSITY-LIPOPROTEIN CHOLESTEROL ; CARDIOVASCULAR RISK REDUCTION ; DE-NOVO LIPOGENESIS ; BEMPEDOIC ACID ; SMALL-MOLECULE ; LDL-C ; LIVER ; PREVENTION ; EFFICACY
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号WOS:000944657900001
源URL[http://119.78.100.183/handle/2S10ELR8/309692]  
专题新药研究国家重点实验室
通讯作者Li, Jingya; Nan, Fajun
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Drug Discovery Shandong Lab, Yantai 264117, Peoples R China
2.Burgeon Therapeut Co Ltd, Shanghai 201203, Peoples R China;
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Xie, Zhifu,Zhang, Mei,Song, Qian,et al. Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia[J]. ACTA PHARMACEUTICA SINICA B,2023,13(2):739-753.
APA Xie, Zhifu.,Zhang, Mei.,Song, Qian.,Cheng, Long.,Zhang, Xinwen.,...&Nan, Fajun.(2023).Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia.ACTA PHARMACEUTICA SINICA B,13(2),739-753.
MLA Xie, Zhifu,et al."Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia".ACTA PHARMACEUTICA SINICA B 13.2(2023):739-753.

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来源：上海药物研究所

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