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])
ISSN0223-5234
EISSN1768-3254
卷号236
发表状态已发表
DOI10.1016/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...
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).
条目包含的文件
文件名称/大小 文献类型 版本类型 开放类型 使用许可
个性服务
查看访问统计
谷歌学术
谷歌学术中相似的文章
[Li, Xing-Zi]的文章
[Jiang, Shi-You]的文章
[Li, Guo-Qiang]的文章
百度学术
百度学术中相似的文章
[Li, Xing-Zi]的文章
[Jiang, Shi-You]的文章
[Li, Guo-Qiang]的文章
必应学术
必应学术中相似的文章
[Li, Xing-Zi]的文章
[Jiang, Shi-You]的文章
[Li, Guo-Qiang]的文章
相关权益政策
暂无数据
收藏/分享
所有评论 (0)
暂无评论
 

除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。