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Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol | |
2022-06-05 | |
发表期刊 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (IF:6.0[JCR-2023],6.1[5-Year]) |
ISSN | 0223-5234 |
EISSN | 1768-3254 |
卷号 | 236 |
发表状态 | 已发表 |
DOI | 10.1016/j.ejmech.2022.114323 |
摘要 | HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of cardiovascular disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (QH536) showed an EC of 0.22 μΜ in promoting HMGCR degradation, which was about 2 times more potent than HMG499 (EC = 0.43 μM). Interestingly, 29 was different from HMG499, it had no side-effect of inducing cholesterol accumulation in cells. Mechanistic studies disclosed that 29 could significantly decrease statin-induced accumulation of HMGCR protein via ubiquitination and degradation of HMGCR through ubiquitin-proteasome pathway and inhibit the cholesterol biosynthesis in cells. Therefore, these heterocyclic ring-fused analogs could be used as promising leads for the development of new types of agents against CVD. Furthermore, 29 also lowered cholesterol levels and suppressed TGFβ1-induced proliferation of LX-2 hepatic stellate cells in a dose-dependent manner. In particular, 29 not only decreased the NASH associated fibrotic mRNA and protein expression of α-SMA, COL1A1, TIMP1 and TGFβ1 but also suppressed cholesterol levels and inflammatory genes of TNF-α, IL-6 an IL-1β in RAW264.7 macrophage cells, indicating that 29 may bring therapeutic benefit to treat NASH. |
关键词 | Cardiovascular disease Cholesterol Degrader HMG-CoA reductase NASH |
URL | 查看原文 |
收录类别 | SCIE ; SCI ; IC |
语种 | 英语 |
资助项目 | National Natural Science Foundation of China["22077035","32070609","32022034"] |
WOS研究方向 | Pharmacology & Pharmacy |
WOS类目 | Chemistry, Medicinal |
WOS记录号 | WOS:000821147500005 |
出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
Scopus 记录号 | 2-s2.0-85127699121 |
来源库 | Scopus |
引用统计 | 正在获取...
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文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/176082 |
专题 | 生命科学与技术学院_PI研究组_戚炜组 生命科学与技术学院_硕士生 |
通讯作者 | Ma, Xin-Ran; Qi, Wei; Qiu, Wen-Wei |
作者单位 | 1.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China 2.Wuhan Univ, Inst Adv Studies, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Peoples R China 3.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China 4.East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China |
通讯作者单位 | 生命科学与技术学院 |
推荐引用方式 GB/T 7714 | Li, Xing-Zi,Jiang, Shi-You,Li, Guo-Qiang,et al. Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,236. |
APA | Li, Xing-Zi.,Jiang, Shi-You.,Li, Guo-Qiang.,Jiang, Qian-Ru.,Li, Jue-Wan.,...&Qiu, Wen-Wei.(2022).Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,236. |
MLA | Li, Xing-Zi,et al."Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 236(2022). |
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