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

• Published in: Nature communications Vol. 9; no. 1; pp. 5138 - 13
• Main Authors: Jiang, Shi-You, Li, Hui, Tang, Jing-Jie, Wang, Jie, Luo, Jie, Liu, Bing, Wang, Jin-Kai, Shi, Xiong-Jie, Cui, Hai-Wei, Tang, Jie, Yang, Fan, Qi, Wei, Qiu, Wen-Wei, Song, Bao-Liang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/109; 13/51; 13/89; 14; 14/19; 14/35; 38/90; 631/45/612/1254; 631/92/287/1197; 692/699/75/2099; 82/47; Accumulation; Animals; Arteriosclerosis; Atherosclerosis; Biosynthesis; Cardiovascular disease; Cardiovascular diseases; Cell Line, Tumor; CHO Cells; Cholesterol; Cholesterol - biosynthesis; Cricetulus; Degradation; Drug Synergism; Humanities and Social Sciences; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA reductase; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Intermediates; Male; Mice; Molecular Structure; multidisciplinary; Organic chemistry; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - prevention & control; Plaques; Proteins; Proteolysis - drug effects; Science; Science (multidisciplinary); Side effects; Statins; Sterols - chemistry; Sterols - pharmacology; Ubiquitination; Ubiquitination - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07590-3

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. Accumulated HMG-CoA reductase (HMGCR) limits the cholesterol-lowering effect of statins via a feedback loop. Here the authors developed a compound that degrades HMGCR, thus decreasing cholesterol levels and reducing atherosclerotic plaques.