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Structure-based discovery of potent USP28 inhibitors derived from Vismodegib

文献类型：期刊论文

作者Zhou, Di1,7; Xu, Zhuo2,4; Huang, Yaodong5,7; Wang, Hui2; Zhu, Xiaoli3,7; Zhang, Wentao5,7; Song, Weiwei1,7; Gao, Tong1,7; Liu, Tongchao3; Wang, Meng6,7
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-06-05
卷号254页码:15
ISSN号0223-5234
关键词USP28 Structure-based Vismodegib derivatives Structure-activity relationships c-Myc
DOI10.1016/j.ejmech.2023.115369
通讯作者Wang, Meng(research@chemvon.com) ; Shi, Li(shili@simm.ac.cn) ; Zhang, Naixia(nxzhang@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要Ubiquitin-specific proteases (USPs) 28 is overexpressed in multiple types of cancers. The development of potent USP28 inhibitors is still in primitive stage. We previously reported our discovery of Vismodegib as a USP28 inhibitor by screening a commercially available drug library. Herein, we report our efforts to solve the cocrystal structure of Vismodegib bound to USP28 for the first time and subsequent structure-based optimization leading to a series of Vismodegib derivatives as potent USP28 inhibitors. Based on the cocrystal structure, elaborative SARs exploration was carried out to afford much more potent USP28 inhibitors than Vismodegib. The repre-sentative compounds 9l, 9o and 9p bearing high potency on USP28 showed high selectivity over USP2, USP7, USP8, USP9x, UCHL3 and UCHL5. The detailed cellular assay suggested that compounds 9l, 9o and 9p could cause cytotoxicity in both human colorectal cancer and lung squamous carcinoma cells and significantly enhance the sensitivity of colorectal cancer cells to Regorafenib. Further immunoblotting analysis indicated that com-pounds 9l, 9o and 9p could dose-dependently down-regulate the cellular level of c-Myc through ubiquitin-proteasome system and anti-cancer effects could mainly be attributed to their inhibition on USP28 but not involving the Hedgehog-Smoothened pathway. Thus, our work provided a series of novel and potent USP28 inhibitors derived from Vismodegib and may contribute to the development of USP28 inhibitors.
WOS关键词INTESTINAL HOMEOSTASIS ; IDENTIFICATION
资助项目National Natural Sci- ence Foundation of China[21977105] ; National Natural Sci- ence Foundation of China[32000890] ; National Natural Sci- ence Foundation of China[32171220] ; Shanghai Municipal Science and Technology Major Project
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:000987188400001
源URL[http://119.78.100.183/handle/2S10ELR8/306517]  
专题中国科学院上海药物研究所
通讯作者Wang, Meng; Shi, Li; Zhang, Naixia; Xiong, Bing
作者单位1.Anhui Univ Chinese Med, 350 Longzihu Rd, Hefei 230012, Anhui, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Analyt Res Ctr Organ & Biol Mol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.Shenyang Pharmaceut Univ, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China
6.Shanghai Chemvon Biotechnol Co Ltd, Shanghai 201202, Peoples R China
7.Yangtze Delta Drug Advnced Res Inst, 100 Dongtinghu Rd, Nantong 226133, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Di,Xu, Zhuo,Huang, Yaodong,et al. Structure-based discovery of potent USP28 inhibitors derived from Vismodegib[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,254:15.
APA Zhou, Di.,Xu, Zhuo.,Huang, Yaodong.,Wang, Hui.,Zhu, Xiaoli.,...&Xiong, Bing.(2023).Structure-based discovery of potent USP28 inhibitors derived from Vismodegib.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,254,15.
MLA Zhou, Di,et al."Structure-based discovery of potent USP28 inhibitors derived from Vismodegib".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 254(2023):15.

入库方式： OAI收割

来源：上海药物研究所

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