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Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial

文献类型：期刊论文

作者Wang, Jiang4,5,6; Zhao, Jing3; Yan, Cong4,6; Xi, Cong4,6; Wu, Chenglin4,6; Zhao, Jingxiang6; Li, Fengwei2; Ding, Yanhua1; Zhang, Rui4,6; Qi, Shankang4,6
刊名CELL METABOLISM
出版日期2022-05-03
卷号34期号:5页码:667-+
ISSN号1550-4131
DOI10.1016/j.cmet.2022.03.006
通讯作者Huang, He(hhuang@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要Developing non-statin-based small compounds to battle the global epidemic of hyperlipidemia remains challenging. Here, we report the discovery of DC371739, an indole-containing tetrahydroisoquinoline compound with promising lipid-lowering effects, both in vitro and in vivo, and with good tolerability in a Phase I clinical trial (NCT04927221). DC371739 significantly reduced the plasma levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides simultaneously in several animal models and showed preliminary positive results in the Phase I trial. Mechanistically, DC371739 acts in a distinct manner from other known lipid-lowering reagents. We show that it physically binds HNF-1a, impeding the transcription of both PCSK9 and ANGPTL3, two genes that are known to contribute to hypercholesterolemia and dyslipidemia. Moreover, the distinct mechanism of action of DC371739 allows its combination with atorvastatin treatment to additively improve dyslipidemia, while providing a potential alternative therapeutic strategy for individuals with statin intolerance.
WOS关键词ANGIOPOIETIN-LIKE 3 ; TETRAHYDROPROTOBERBERINE DERIVATIVES ; DOPAMINE D-1 ; BIOLOGICAL EVALUATION ; GENE-EXPRESSION ; ANGPTL3 ; DESIGN ; PCSK9 ; INHIBITION ; MUTATIONS
资助项目National Natural Science Foundation of China[91953108] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973164] ; National Natural Science Foundation of China[21877118] ; Shanghai Pujiang Program[19PJ1411200] ; Taishan Scholars Program of Shandong Province[tsqn201909004] ; Shanghai Municipal Science and Technology Major Project ; Lingang Laboratory[LG202103-03-03]
WOS研究方向Cell Biology ; Endocrinology & Metabolism
语种英语
出版者CELL PRESS
WOS记录号WOS:000802270200006
源URL[http://119.78.100.183/handle/2S10ELR8/301237]  
专题新药研究国家重点实验室
通讯作者Huang, He; Liu, Hong
作者单位1.First Hosp Jilin Univ, Jilin 130021, Jilin, Peoples R China
2.Shandong Univ, Helmholtz Int Lab, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Lingang Lab, Shanghai 200031, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Jiang,Zhao, Jing,Yan, Cong,et al. Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial[J]. CELL METABOLISM,2022,34(5):667-+.
APA Wang, Jiang.,Zhao, Jing.,Yan, Cong.,Xi, Cong.,Wu, Chenglin.,...&Liu, Hong.(2022).Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial.CELL METABOLISM,34(5),667-+.
MLA Wang, Jiang,et al."Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial".CELL METABOLISM 34.5(2022):667-+.

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来源：上海药物研究所

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