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Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel HsClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma

文献类型：期刊论文

作者Sun, Mingyang8; Chen, Beijing8; Teng, Dan4,6,9; Zhao, Hongshen8; Liao, Yilie8; Zhang, Chun2,8; Huang, Qi8; Ma, Huicong2,8; Wang, Chongyu2,8; Lin, Xinyi8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-02-12
卷号68期号:4页码:4287-4307
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02016
英文摘要The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During the development of HsClpP activators, we found that incorporating methyl groups into the bicyclic imipridone scaffolds significantly enhanced the activator activity at the enzymatic level. Further structure-activity relationship studies led to the identification of a highly promising compound, CLPP-2068, which exhibited an EC50 value of 50.4 nM. Cryo-electron microscopy techniques and computational analyses demonstrated that the introduction of methyl groups facilitated the formation of additional CH-pi interactions between CLPP-2068 and HsClpP, thereby lowering the energy barriers during the binding process. Furthermore, additional pharmaceutical analyses indicated that CLPP-2068 exhibited favorable pharmacokinetic properties and effectively mitigated the potential hERG toxicity observed in imipridone-based HsClpP activators. Collectively, CLPP-2068, developed using the magic methylation strategy, holds potential as a therapeutic agent for the treatment of diffuse large B-cell lymphoma, thereby expanding the clinical indications for HsClpP activators.
WOS关键词CLPP PROTEASE ; MITOCHONDRIAL ; VISUALIZATION ; THERAPEUTICS ; DERIVATIVES ; INHIBITION ; REDUCTASE ; ML-236A ; MODEL ; CIPP
资助项目National Natural Science Foundation of China[2019B090904008] ; Guangdong High-level New RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute[CXTD2022011] ; Guangdong High-level Innovative Research Institute[CXTD2023010] ; Creative Research Group of Zhongshan City[82304539] ; Creative Research Group of Zhongshan City[82122067] ; Creative Research Group of Zhongshan City[32171189] ; National Natural Science Foundation of China[GZC20232846] ; Postdoctoral Fellowship Program of CPSF[2023YFC3605504] ; National Key R&D Program of China[2021278] ; Youth Innovation Promotion Association of CAS ; Shanghai Institute of Material Medica
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001419507100001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/316254]  
专题新药研究国家重点实验室
通讯作者Zheng, Mingyue; Yin, Wanchao; Zhou, Yubo; Li, Jia; Wang, Mingliang
作者单位1.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou 310018, Peoples R China
2.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
8.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Mingyang,Chen, Beijing,Teng, Dan,et al. Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel HsClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(4):4287-4307.
APA Sun, Mingyang.,Chen, Beijing.,Teng, Dan.,Zhao, Hongshen.,Liao, Yilie.,...&Wang, Mingliang.(2025).Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel HsClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma.JOURNAL OF MEDICINAL CHEMISTRY,68(4),4287-4307.
MLA Sun, Mingyang,et al."Harnessing the Magic Methyl Effect: Discovery of CLPP-2068 as a Novel HsClpP Activator for the Treatment of Diffuse Large B-Cell Lymphoma".JOURNAL OF MEDICINAL CHEMISTRY 68.4(2025):4287-4307.

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来源：上海药物研究所

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