2. Academic Validation
  3. Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol

Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol

  • Nat Commun. 2018 Dec 3;9(1):5138. doi: 10.1038/s41467-018-07590-3.
Shi-You Jiang 1,  Hui Li 2,  Jing-Jie Tang 3,  Jie Wang 2,  Jie Luo 1,  Bing Liu 2,  Jin-Kai Wang 1,  Xiong-Jie Shi 1,  Hai-Wei Cui 2,  Jie Tang 2,  Fan Yang 2,  Wei Qi 4,  Wen-Wei Qiu 5,  Bao-Liang Song 6
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, 430072, Wuhan, China.
  • 2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 200241, Shanghai, China.
  • 3 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 200241, Shanghai, China. wwqiu@chem.ecnu.edu.cn.
  • 6 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, 430072, Wuhan, China. blsong@whu.edu.cn.
PMID: 30510211 DOI: 10.1038/s41467-018-07590-3
Abstract

Statins are inhibitors of HMG-CoA reductase, the rate-limiting Enzyme of Cholesterol biosynthesis, and have been clinically used to treat Cardiovascular Disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that Cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure-activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower Cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating Cardiovascular Disease.

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