Discovery of novel USP8 inhibitors via Ubiquitin-Rho-110 fluorometric assay based high throughput screening
文献类型：期刊论文
| 作者 | Han, Jie2,3; Tian, Yucheng1; Yu, Liang2 ; Zhang, Qilin4; Xu, Xi1; Zhang, Yichao4; Wang, Jubo1; Ma, Zengyi4; Bian, Jinlei1; Luo, Cheng2
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| 刊名 | BIOORGANIC CHEMISTRY
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| 出版日期 | 2020-08-01 |
| 卷号 | 101页码:9 |
| 关键词 | Ubiquitination High throughput screening Drug discovery USP8 |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2020.103962 |
| 通讯作者 | Zhao, Yao(zhaoyaohs@vip.sina.com) ; Li, Zhiyu(zhiyuli@cpu.edu.cn) ; Ding, Hong(hding@simm.ac.cn) |
| 英文摘要 | USP8, one member of deubiquitinating enzymes (DUBs) families, maintains the ubiquitination level of EGFR and regulates the downstream signaling pathways. The deregulation of USP8 has been implicated in many human diseases, especially in cancer. Therefore, USP8 has been identified as a promising target for drug design. Herein, via high throughput screening based on Ubiquitin-rhodamine-110 (Ubiquitin-Rho-110) fluorometric activity assay, we discovered a novel inhibitor DC-U43. By structure optimization, DC-U43-10 reached a half-maximal inhibitory concentration (IC50) value of 2.6 +/- 1.1 mu M and exhibited 10-fold selectivity against USP7. The binding between DC-U43-10 and USP8 was validated by surface plasmon resonance (SPR) assay with a K-D value of 10.5 +/- 3.7 mu M. It also inhibited the colony formation of H1975 cells. Hence, DC-U43-10 represents a kind of USP8 inhibitors with novel scaffold and has broad prospects for being a probe for USP8-related academic and clinical research. |
| WOS关键词 | DEUBIQUITINATING ENZYME ; MUTATIONS ; SYSTEM ; CHAINS ; RESISTANCE ; BINDING ; UBPY |
| 资助项目 | Ministry of Science and Technology of China (National Key R&D Program of China)[2017YFB0202600] ; Personalized Medicines Molecular Signature-based Drug Discovery and Development (Strategic Priority Research Program of the Chinese Academy of Sciences)[XDA12020368] ; Chang Jiang Scholars Program ; National Program for Support of Top-Notch Young Professionals ; National Science Fund for Distinguished Young Scholars[81725011] ; National Natural Science Foundation of China[81802495] ; Shanghai Sailing Program[18YF1403400] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000552629800006 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292120]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Yao; Li, Zhiyu; Ding, Hong |
| 作者单位 | 1.China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 4.Fudan Univ, Huashan Hosp, Shanghai Med Coll, Dept Neurosurg, Shanghai 200040, Peoples R China |
| 推荐引用方式 GB/T 7714 | Han, Jie,Tian, Yucheng,Yu, Liang,et al. Discovery of novel USP8 inhibitors via Ubiquitin-Rho-110 fluorometric assay based high throughput screening[J]. BIOORGANIC CHEMISTRY,2020,101:9. |
| APA | Han, Jie.,Tian, Yucheng.,Yu, Liang.,Zhang, Qilin.,Xu, Xi.,...&Ding, Hong.(2020).Discovery of novel USP8 inhibitors via Ubiquitin-Rho-110 fluorometric assay based high throughput screening.BIOORGANIC CHEMISTRY,101,9. |
| MLA | Han, Jie,et al."Discovery of novel USP8 inhibitors via Ubiquitin-Rho-110 fluorometric assay based high throughput screening".BIOORGANIC CHEMISTRY 101(2020):9. |
入库方式： OAI收割
来源：上海药物研究所
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