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Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression

文献类型：期刊论文

作者Lu, Yang10; Gao, Jian10; Wang, Peipei3,8,9; Chen, Haifeng10; He, Xinjun10; Luo, Mengxin10; Guo, Yu10; Li, Linjie10; Zhuang, Weihao10; Zhang, Bo1,2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-06-05
卷号272页码:21
关键词Hepatocellular carcinoma Ubiquitin-specific protease 10 Deubiquitination Selectivity
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.116468
通讯作者Dong, Xiaowu(dongxw@zju.edu.cn) ; Che, Jinxin(chejx@zju.edu.cn)
英文摘要High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes -associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S -phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.
WOS关键词USP10 ; P53
资助项目National Natural Science Foundation of China[82173660] ; Natural Science Fund for Distinguished Young Scholars of Zhejiang Province[LR21H300003] ; Zhejiang Provincial Key Research & Development Plan[2023C03111] ; Zhejiang Provincial Key Research & Development Plan[2022C03155] ; Zhejiang Provincial Key Research & Development Plan[2023C03112]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001240368300004
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/311606]  
专题新药研究国家重点实验室
通讯作者Dong, Xiaowu; Che, Jinxin
作者单位1.Zhejiang Univ, Sch Med, Canc Ctr, Hangzhou 310006, Zhejiang, Peoples R China
2.Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Sch Med,Dept Clin Pharmacol, Key Lab Clin Canc Pharmacol & Toxicol Res Zhejiang, Hangzhou 310006, Zhejiang, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Shanghai 528400, Guangdong, Peoples R China
5.Zhejiang Univ, Natl Key Lab Adv Drug Delivery & Release Syst, Hangzhou 310058, Peoples R China
6.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China
7.Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Pharm, Hangzhou 310009, Peoples R China
8.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
10.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Yang,Gao, Jian,Wang, Peipei,et al. Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,272:21.
APA Lu, Yang.,Gao, Jian.,Wang, Peipei.,Chen, Haifeng.,He, Xinjun.,...&Che, Jinxin.(2024).Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,272,21.
MLA Lu, Yang,et al."Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 272(2024):21.

入库方式： OAI收割

来源：上海药物研究所

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