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Development of novel epoxyketone macrocyclic peptidyl proteasome inhibitors through OPA-mediated one-step cyclization of unprotected peptides

文献类型：期刊论文

作者Zeng, Gongruixue7,10; Xu, Gaoya2,3,9; Gao, Lixin2,9; Zheng, Xiaoli10; Chi, Xinglong8; Shen, Zheyuan7; Cao, Yu6; Xi, Jianjun6; Che, Jinxin7; Dong, Xiaowu7
刊名BIOORGANIC CHEMISTRY
出版日期2025-03-01
卷号156页码:16
关键词Proteasome inhibitors Macrocycle Stability Anti-cancer activities
ISSN号0045-2068
DOI10.1016/j.bioorg.2025.108180
通讯作者Li, Jia(jli@simm.ac.cn) ; Zhang, Jiankang(zhang_jk@hzcu.edu.cn)
英文摘要Cyclization is a pivotal strategy for enhancing the drug-like characteristics of polypeptides. To develop potent and metabolically stable proteasome inhibitors, we generated a macrocyclic peptide skeleton using a straightforward and efficient cyclization strategy. Subsequent stability assessments confirmed the practicality of this approach. Leveraging this skeleton, we designed and synthesized a series of epoxyketone macrocyclic peptidyl proteasome inhibitors. Approximately half of these compounds showcased robust inhibitory potency, with IC50 values below 200 nM against chymotrypsin-like (ChT-L, beta 5) activity. Notably, compounds 6f, 6g, and 6m demonstrated pronounced anti-proliferative activities at low nanomolar concentrations against three hematoma cell lines (RPMI-8226, RS4;11, and MV-4-11) as well as the NCI-H1299 cell line. These findings highlight the potential of these cyclic peptides to bolster the stability of proteasome inhibitors, thereby providing valuable insights for the advancement of innovative proteasome inhibitor therapies.
WOS关键词20S PROTEASOME ; COMPLEX
资助项目Zhejiang Provincial Natural Science Foundation of China[LY24H300003] ; Zhejiang Provincial Natural Science Foundation of China[LTGY24B020001] ; Zhejiang Provincial Natural Science Foundation of China[MS25B020004] ; Zhongshan Science and Technology Bureau[CXTD2023009] ; Hangzhou Natural Science Foundation[2024SZRYBH300001] ; Interdisciplinary Foundation from Hangzhou City University[X-202305] ; Medical Health Science and Technology Project of Zhejiang Provincial Health Commission[2024KY210]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001409645000001
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/315962]  
专题中国科学院上海药物研究所
通讯作者Li, Jia; Zhang, Jiankang
作者单位1.Hangzhou City Univ, Sch Med, Hangzhou 310015, Zhejiang Provin, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
6.Hangzhou Xixi Hosp, Dept Pharmaceut Preparat, Hangzhou 310023, Zhejiang Provin, Peoples R China
7.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang Provin, Peoples R China
8.Hangzhou Med Coll, Ctr Safety Evaluat & Res, Hangzhou, Zhejiang, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
10.Hangzhou City Univ China, Key Lab Novel Targets & Drug Study Neural Repair Z, Sch Med, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Zeng, Gongruixue,Xu, Gaoya,Gao, Lixin,et al. Development of novel epoxyketone macrocyclic peptidyl proteasome inhibitors through OPA-mediated one-step cyclization of unprotected peptides[J]. BIOORGANIC CHEMISTRY,2025,156:16.
APA Zeng, Gongruixue.,Xu, Gaoya.,Gao, Lixin.,Zheng, Xiaoli.,Chi, Xinglong.,...&Zhang, Jiankang.(2025).Development of novel epoxyketone macrocyclic peptidyl proteasome inhibitors through OPA-mediated one-step cyclization of unprotected peptides.BIOORGANIC CHEMISTRY,156,16.
MLA Zeng, Gongruixue,et al."Development of novel epoxyketone macrocyclic peptidyl proteasome inhibitors through OPA-mediated one-step cyclization of unprotected peptides".BIOORGANIC CHEMISTRY 156(2025):16.

入库方式： OAI收割

来源：上海药物研究所

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