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

  • Cell Metab. 2022 May 3;34(5):667-680.e6. doi: 10.1016/j.cmet.2022.03.006.
Jiang Wang  1 ,  Jing Zhao  2 ,  Cong Yan  3 ,  Cong Xi  3 ,  Chenglin Wu  3 ,  Jingxiang Zhao  4 ,  Fengwei Li  5 ,  Yanhua Ding  6 ,  Rui Zhang  3 ,  Shankang Qi  3 ,  Xingjun Li  4 ,  Chao Liu  5 ,  Wanting Hou  4 ,  Hong Chen  6 ,  Yiping Wang  3 ,  Dalei Wu  5 ,  Kaixian Chen  3 ,  Hualiang Jiang  7 ,  He Huang  8 ,  Hong Liu  9
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Lingang Laboratory, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
  • 6. The First Hospital of Jilin University, Jilin 130021, China.
  • 7. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Lingang Laboratory, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 8. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  • 9. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: [email protected].
PMID: 35427476 DOI: 10.1016/j.cmet.2022.03.006
Abstract

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-1α, 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.

Keywords
ANGPTL3; HNF-1α; PCSK9; atorvastatin; combination treatment; hyperlipidemia; tetrahydroisoqinoline.
Products