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Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity

文献类型：期刊论文

作者Chen, Beijing2,3; Sun, Mingyang2; Zhang, Chun2,4; Huang, Qi2,5; Teng, Dan6; Hu, Linghao1,2; Ma, Huicong2,4; Lin, Xinyi2,7; Huang, Zan2; Gui, Renzhao2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-11-22
页码21
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c01605
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Wang, Mingliang(wangmingliang@simm.ac.cn)
英文摘要Human sapiens caseinolytic protease P (ClpP) is essential for maintaining mitochondrial proteome homeostasis, and its activation is increasingly recognized as a promising cancer therapy strategy. Herein, based on structure-guided drug design, we discovered a series of potent ClpP activators by introducing a methyl group to the imipridone scaffold of the ClpP activator ONC201 in Phase III clinical trials. Through structural optimization of the lead compound, the most optimal compound, CLPP-1071, exhibited exceptionally potent ClpP agonistic activity (EC50 = 23.5 nM, 107.1-fold stronger than ONC201) and inhibited the proliferation of HL60 cells (IC50 = 4.6 nM, 169.2-fold stronger than ONC201). CLPP-1071 possesses good pharmacokinetic properties and effectively prolongs the lifespan in the MOLM13 and HL60 xenograft models in mice through oral administration. CLPP-1071 is the most potent and orally efficacious ClpP activator reported to date.
WOS关键词COMPLEX I ; MITOCHONDRIA ; PROTEASE ; INHIBITION ; DISEASES ; ANALOGS ; FAMILY ; CANCER ; CIPP
资助项目Shanghai Science and Technology Development Foundation[2019B090904008] ; Guangdong High-level New RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute[CXTD2022011] ; Creative Research Group of Zhongshan City (Lingnan Pharmaceutical Research and Innovation team)[82304539] ; National Natural Science Foundation of China[22YF1457600] ; Shanghai Science and Technology Development Funds[2023M733629] ; China Postdoctoral Science Foundation[GZC20232846] ; Postdoctoral Fellowship Program of CPSF
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001362142600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/314683]  
专题中国科学院上海药物研究所
通讯作者Zhou, Yubo; Li, Jia; Wang, Mingliang
作者单位1.Chinese Acad Sci, Dept Med Chem, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
3.Guizhou Med Univ, Sch Pharm, Guiyang 550014, Peoples R China
4.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China
5.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
7.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Guangdong, Peoples R China
8.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Beijing,Sun, Mingyang,Zhang, Chun,et al. Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:21.
APA Chen, Beijing.,Sun, Mingyang.,Zhang, Chun.,Huang, Qi.,Teng, Dan.,...&Wang, Mingliang.(2024).Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity.JOURNAL OF MEDICINAL CHEMISTRY,21.
MLA Chen, Beijing,et al."Discovery of CLPP-1071 as an Exceptionally Potent and Orally Efficacious Human ClpP Activator with Strong In Vivo Antitumor Activity".JOURNAL OF MEDICINAL CHEMISTRY (2024):21.

入库方式： OAI收割

来源：上海药物研究所

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