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Metabolism guided optimization of peptidomimetics as non-covalent proteasome inhibitors for cancer treatment

文献类型：期刊论文

作者Cao, Yu2,3; Tu, Yutong4,5; Fu, Liping6; Yu, Qian2,3; Gao, Lixin4,7; Zhang, Mengmeng4; Zeng, Linghui2; Zhang, Chong2; Shao, Jiaan2; Zhu, Huajian2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-04-05
卷号233页码:18
ISSN号0223-5234
关键词Metabolism Design Proteasome inhibitors Non-covalent Multiple myeloma
DOI10.1016/j.ejmech.2022.114211
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhang, Jiankang(jk@zucc.edu.cn)
英文摘要A series of novel non-covalent peptidomimetic proteasome inhibitors possessing bulky group at the C-terminus and N-alkylation at the N-terminus were designed with the aim to increase metabolic stabilities in vivo. All the target compounds were screened for their inhibitory activities against human 20S proteasome, and most analogs exhibited notable potency compared with the positive control bortezomib with IC50 values lower than 10 nM, which also displayed potent cytotoxic activities against multiple myeloma (MM) cell lines and human acute myeloid leukemia (AML) cells. Furthermore, whole blood stability and in vivo proteasome inhibitory activity experiments of selected compounds were conducted for further evaluation, and the representative compound 43 (IC50 = 8.39 & PLUSMN; 2.32 nM, RPMI-8226: IC50 = 15.290 & PLUSMN; 2.281 nM, MM-1S: IC50 = 9.067 & PLUSMN; 3.103 nM, MV-4-11: IC50 = 2.464 & PLUSMN; 0.713 nM) revealed a half-life extension of greater than 9-fold (329.21 min VS 36.79 min) and potent proteasome inhibitory activity in vivo. The positive results confirmed the reliability of the metabolism guided optimization strategy, and the analogs discovered are potential leads for exploring new anti-MM drugs. (c) 2022 Elsevier Masson SAS. All rights reserved.
WOS关键词IMMUNOPROTEASOME ; PEPTIDES ; SAFETY
资助项目National Natural Science Foundation of China[81803432] ; Science and Technology Department of Zhejiang Province[LGF20H 30003] ; Second Round of Excellent Innovation Team of Hangzhou Municipal University
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:000765973200006
源URL[http://119.78.100.183/handle/2S10ELR8/300200]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Zhang, Jiankang
作者单位1.Chinese Acad Sci, Shanghai Inst Metria Med, Zhongshan Inst Drug Discovery, Guangzhou 528400, Guangdong, Peoples R China
2.Zhejiang Univ City Coll, Sch Med, Hangzhou 310015, Peoples R China
3.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Zhejiang Chinese Med Univ, Shaoxing TCM Hosp, Dept Pharm, Shaoxing 312000, Peoples R China
7.Jiangnan Univ, Sch Pharmaceut Sci, Wuxi 214122, Jiangsu, Peoples R China
8.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310000, Peoples R China
推荐引用方式
GB/T 7714		 Cao, Yu,Tu, Yutong,Fu, Liping,et al. Metabolism guided optimization of peptidomimetics as non-covalent proteasome inhibitors for cancer treatment[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,233:18.
APA Cao, Yu.,Tu, Yutong.,Fu, Liping.,Yu, Qian.,Gao, Lixin.,...&Zhang, Jiankang.(2022).Metabolism guided optimization of peptidomimetics as non-covalent proteasome inhibitors for cancer treatment.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,233,18.
MLA Cao, Yu,et al."Metabolism guided optimization of peptidomimetics as non-covalent proteasome inhibitors for cancer treatment".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 233(2022):18.

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来源：上海药物研究所

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