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

Shi-You Jiang, Hui Li, Jing-Jie Tang, Jie Wang, Jie Luo, Bing Liu, Jin-Kai Wang, Xiong-Jie Shi, Hai-Wei Cui, Jie Tang, Fan Yang, Wei Qi, Wen-Wei Qiu () and Bao-Liang Song ()
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Shi-You Jiang: Wuhan University
Hui Li: East China Normal University
Jing-Jie Tang: Chinese Academy of Sciences
Jie Wang: East China Normal University
Jie Luo: Wuhan University
Bing Liu: East China Normal University
Jin-Kai Wang: Wuhan University
Xiong-Jie Shi: Wuhan University
Hai-Wei Cui: East China Normal University
Jie Tang: East China Normal University
Fan Yang: East China Normal University
Wei Qi: ShanghaiTech University
Wen-Wei Qiu: East China Normal University
Bao-Liang Song: Wuhan University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07590-3

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