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Assessment of the structure-activity relationship and antileukemic activity of diacylpyramide compounds as human ClpP agonists

文献类型：期刊论文

作者Zhang, Ranran1,2; Wang, Pengyu1,2; Wei, Bingyan1,2,3; Chen, Liang2,3; Song, Xiaomin1,2; Pan, Yihui1,2,3; Li, Jiahui2,3; Gan, Jianhua4; Zhang, Tao2; Yang, Cai-Guang1,2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-10-05
卷号258页码:17
ISSN号0223-5234
关键词ClpP agonists Structure-activity relationship Mitochondrial respiratory chain Antileukemic therapy
DOI10.1016/j.ejmech.2023.115577
通讯作者Zhang, Tao(zhangtao@simm.ac.cn) ; Yang, Cai-Guang(yangcg@simm.ac.cn)
英文摘要Human caseinolytic protease P (ClpP) is required for the regulatory hydrolysis of mitochondrial proteins. Allosteric ClpP agonists dysfunctionally activate mitochondrial ClpP in antileukemic therapies. We previously developed ZG111, a potent ClpP agonist derived from ICG-001, inhibits the proliferation of pancreatic ductal adenocarcinoma cell lines in vitro and in vivo by degrading respiratory chain complex proteins. Herein, we studied the structure-activity relationships of ICG-001 analogs as antileukemia agents. Compound ZG36 exhibited improved stabilization effects on the thermal stability of ClpP in acute myeloid leukemia (AML) cell lines compared with the stabilization effects of ZG111, indicating a direct binding between ZG36 and ClpP. Indeed, the resolved ZG36/ClpP structural complex reveals the mode of action of ZG36 during ClpP binding. Compound ZG36 nonselectively degrades respiratory chain complexes and decreases the mitochondrial DNA, eventually leading to the collapse of mitochondrial function and leukemic cell death. Finally, ZG36 treatment inhibited 3-D cell growth in vitro and suppressed the tumorigenesis of AML cells in xenografted mice models. Collectively, we developed a new class of human ClpP agonists that can be used as potential antileukemic therapies.
WOS关键词THERAPEUTIC STRATEGY ; MITOCHONDRIAL CLPP ; MOLECULE INHIBITOR ; PROTEASE
资助项目National Key Research and Development Program of China[2022YFC2705005] ; National Natural Science Foun-dation of China[22107109] ; National Natural Science Foun-dation of China[22037007] ; China National Program for Innovative Talents[BX20220321] ; Youth Innovation Promotion Association of CAS[2023297]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001024815100001
源URL[http://119.78.100.183/handle/2S10ELR8/306424]  
专题新药研究国家重点实验室
通讯作者Zhang, Tao; Yang, Cai-Guang
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Ranran,Wang, Pengyu,Wei, Bingyan,et al. Assessment of the structure-activity relationship and antileukemic activity of diacylpyramide compounds as human ClpP agonists[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,258:17.
APA Zhang, Ranran.,Wang, Pengyu.,Wei, Bingyan.,Chen, Liang.,Song, Xiaomin.,...&Yang, Cai-Guang.(2023).Assessment of the structure-activity relationship and antileukemic activity of diacylpyramide compounds as human ClpP agonists.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,258,17.
MLA Zhang, Ranran,et al."Assessment of the structure-activity relationship and antileukemic activity of diacylpyramide compounds as human ClpP agonists".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 258(2023):17.

入库方式： OAI收割

来源：上海药物研究所

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