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A shape complementarity strategy based on NCA029 enables potent HsClpP agonists for the treatment of small cell lung carcinoma

文献类型：期刊论文

作者Li, Linjie2,3,4; Luo, Baozhu2,3,4; Wang, Xudong5,6; Jian, Zhongyu7; Liu, Hong2,3,4; Ren, Bo2,3,4; Qiao, Wenliang8; Luo, Youfu2,3,4,9; Yang, Tao1,2,3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-12-05
卷号299页码:26
关键词HsClpP Shape complementarity Small cell lung carcinoma
ISSN号0223-5234
DOI10.1016/j.ejmech.2025.118008
英文摘要Owing to its essential role in maintaining mitochondrial homeostasis, activation of HsClpP is potentially a promising strategy for treating a wide range of cancers, including small cell lung carcinoma (SCLC). In this work, by using a shape complementarity strategy, we designed and synthesized a series of HsClpP agonist based on NCA029, a non-imipridone HsClpP agonist identified in our previous work. Among these derivatives, compound 8o exhibited approximately 5-fold greater binding affinity than NCA029 with HsClpP due to attachment of an additional ring structure at the R-position of NCA029's double bond. It potently inhibited SCLC cells, such as H69 cells (8o: IC50 = 0.17 mu M; NCA029: IC50 = 5.04 mu M), and H82 cells (8o: IC50 = 0.19 mu M; NCA029: IC50 = 1.04 mu M). In addition, 8o exerted improved safety profiles than NCA029 in vitro and in vivo. Furthermore, compound 8o, which exhibits favorable pharmacokinetic properties, significantly inhibited tumor growth in non-SMC xenograft models, achieving a tumor growth inhibition rate of up to 63.01 %.
WOS关键词CANCER ; METABOLISM
资助项目Natural Science Foundation of Sichuan Province[2024NSFSC1146] ; National Nat-ural Science Foundation of China[22307128] ; Hohhot Science and Technology Bureau
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001580970200004
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/321546]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Qiao, Wenliang; Luo, Youfu; Yang, Tao
作者单位1.Sichuan Univ, West China Hosp, Inst Immunol & Inflammat, Frontiers Sci Ctr Dis Related Mol Network, Chengdu 610041, Peoples R China
2.Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Peoples R China
3.Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
4.Sichuan Univ, West China Hosp, Lab Human Dis & Immunotherapy, Chengdu 610041, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Sichuan Univ, West China Hosp, Inst Urol, State Key Dept Urol,Lab Reconstruct Urol, Chengdu 610041, Sichuan, Peoples R China
8.Sichuan Univ, West China Hosp, Dept Lung Canc Ctr, West China Med Sch,Lab Lung Canc, Chengdu, Peoples R China
9.Mitor Inner Mongolia Pharmaceut Co Ltd, Hohho 010090, Peoples R China
推荐引用方式
GB/T 7714		 Li, Linjie,Luo, Baozhu,Wang, Xudong,et al. A shape complementarity strategy based on NCA029 enables potent HsClpP agonists for the treatment of small cell lung carcinoma[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,299:26.
APA Li, Linjie.,Luo, Baozhu.,Wang, Xudong.,Jian, Zhongyu.,Liu, Hong.,...&Yang, Tao.(2025).A shape complementarity strategy based on NCA029 enables potent HsClpP agonists for the treatment of small cell lung carcinoma.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,299,26.
MLA Li, Linjie,et al."A shape complementarity strategy based on NCA029 enables potent HsClpP agonists for the treatment of small cell lung carcinoma".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 299(2025):26.

入库方式： OAI收割

来源：上海药物研究所

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