Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol

doi:10.1016/j.ejmech.2022.114323

	Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol
	Li, Xing-Zi 1; Jiang, Shi-You 2; Li, Guo-Qiang 3,4; Jiang, Qian-Ru 1; Li, Jue-Wan5 ; Li, Chen-Chen 1; Han, Yu-Qin 2; Song, Bao-Liang 2; Ma, Xin-Ran 3,4; Qi, Wei5 ; Qiu, Wen-Wei 1
	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
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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).