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Otilonium Bromide acts as a selective USP28 inhibitor and exhibits cytotoxic activity against multiple human cancer cell lines

文献类型：期刊论文

作者Xu, Zhuo2; Wang, Hui2,3; Meng, Qian1; Ding, Yiluan2; Zhu, Mengying2,3; Zhou, Hu1,3; Zhang, Naixia2,3; Shi, Li2
刊名BIOCHEMICAL PHARMACOLOGY
出版日期2023-09-01
卷号215页码:14
ISSN号0006-2952
关键词Otilonium Bromide Deubiquitinase USP28 Selective inhibitor
DOI10.1016/j.bcp.2023.115746
通讯作者Zhang, Naixia(nxzhang@simm.ac.cn) ; Shi, Li(shili@simm.ac.cn)
英文摘要USP28 contributes to tumorigenesis through modulating the lifespan of oncogenic factors such as c-Myc and & UDelta;Np63, and it has been identified as a potential target for anti-cancer drug development. Currently, although quite a number of USP28 inhibitors have been developed, they all are still in preclinical research stage. Besides, none of them exhibits satisfying inhibition selectivity against USP28 over its closest homologue USP25. Here in this manuscript, a high-throughput screening aiming to discover USP28 inhibitors with novel scaffold and enhanced inhibition selectivity were conducted. After the primary screening and the second round of validation, Otilonium Bromide, an approved drug for treating irritable bowel syndrome, was identified to inhibit USP28 & PRIME;s activity with the IC50 value at 6.90 & PLUSMN; 0.90 & mu;M. Besides, the drug exhibits a 3-4 folds inhibition selectivity against USP28 over USP25. According to the enzymatic kinetics analysis data and the hydrogen-deuterium exchange mass spectrometry results, Otilonium Bromide could bind to the allosteric pocket of USP28 and inhibit its activity in a reversible and non-competitive mode. The following performed cell-based assays revealed that the drug could cause cytotoxicity against human colorectal cancer cells and lung squamous carcinoma cells potentially through down-regulating USP28 & PRIME;s oncogenic substrates c-Myc and/or & UDelta;Np63. Meanwhile, since Otilonium Bromide has been found to preferentially distribute to gastrointestinal tissues, we then evaluated its potential in the combination treatment of colorectal cancer cells with Regorafenib, which is an approved drug for colorectal cancer therapy. As expected, Otilonium Bromide could significantly enhance the sensitivity of colorectal cancer cells to Regorafenib.
WOS关键词INTESTINAL HOMEOSTASIS ; UBIQUITIN ; FBW7
资助项目National Natural Science Foundation of China[21977105] ; National Natural Science Foundation of China[32000890] ; National Natural Science Foundation of China[32171220] ; National Natural Science Foundation of China[22107111] ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号WOS:001063289200001
源URL[http://119.78.100.183/handle/2S10ELR8/306167]  
专题新药研究国家重点实验室
通讯作者Zhang, Naixia; Shi, Li
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, State Key Lab Chem Biol, Analyt Res Ctr Organ & Biol Mol, Shanghai Inst Mat Med, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Zhuo,Wang, Hui,Meng, Qian,et al. Otilonium Bromide acts as a selective USP28 inhibitor and exhibits cytotoxic activity against multiple human cancer cell lines[J]. BIOCHEMICAL PHARMACOLOGY,2023,215:14.
APA Xu, Zhuo.,Wang, Hui.,Meng, Qian.,Ding, Yiluan.,Zhu, Mengying.,...&Shi, Li.(2023).Otilonium Bromide acts as a selective USP28 inhibitor and exhibits cytotoxic activity against multiple human cancer cell lines.BIOCHEMICAL PHARMACOLOGY,215,14.
MLA Xu, Zhuo,et al."Otilonium Bromide acts as a selective USP28 inhibitor and exhibits cytotoxic activity against multiple human cancer cell lines".BIOCHEMICAL PHARMACOLOGY 215(2023):14.

入库方式： OAI收割

来源：上海药物研究所

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