Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression
文献类型：期刊论文
| 作者 | Tian, Yucheng1; Liu, Kang1; Liu, Ruoyi1; Qiu, Zhixia1; Xu, Yifan1; Wei, Wei1; Xu, Xi1; Wang, Jubo1; Ding, Hong2 ; Li, Zhiyu1
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2022-07-14 |
| 卷号 | 65期号:13页码:8914-8932 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c00013 |
| 文献子类 | Article |
| 英文摘要 | Ubiquitin-specific protease 8 (USP8), belonging to the deubiquitinase family, has been implicated to be closely related to the occurrence of many malignant tumors, but only a few USP8-targeting inhibitors have been reported to date. In this study, we present virtual screening to discover novel hit candidates that inhibit the catalytic activity of USP8. Exploration of the structure-activity relationship led to the identification of compound DC-U4106, which binds to USP8 with a K-D value of 4.7 mu M and is selective over USP2 and USP7. Western blotting and immunoprecipitation showed that DC-U4106 could target the ubiquitin pathway and facilitate the degradation of ER alpha. In a xenograft tumor model, DC-U4106 also significantly inhibited tumor growth with minimal toxicity. Overall, our findings suggest that DC-U4106 is a promising drug candidate and targeting the USP8-ER alpha complex could be a new approach to treat ER-positive or drug-resistant breast cancer. |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000827484000001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309328]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Ding, Hong; Li, Zhiyu; Bian, Jinlei |
| 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, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tian, Yucheng,Liu, Kang,Liu, Ruoyi,et al. Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(13):8914-8932. |
| APA | Tian, Yucheng.,Liu, Kang.,Liu, Ruoyi.,Qiu, Zhixia.,Xu, Yifan.,...&Bian, Jinlei.(2022).Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression.JOURNAL OF MEDICINAL CHEMISTRY,65(13),8914-8932. |
| MLA | Tian, Yucheng,et al."Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression".JOURNAL OF MEDICINAL CHEMISTRY 65.13(2022):8914-8932. |
入库方式： OAI收割
来源：上海药物研究所
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