Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors
文献类型：期刊论文
| 作者 | Chen, Danqi1 ; Shen, Aijun2; Li, Jian3; Shi, Feng1; Chen, Wuyan4; Ren, Jing1; Li, Hongchun2; Xu, Yechun4; Wang, Xin1; Yang, Xinying2
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2014-11-24 |
| 卷号 | 87页码:765-781 |
| 关键词 | HSP90 Fragment-based drug discovery Crystallography |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2014.09.065 |
| 文献子类 | Article |
| 英文摘要 | HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 mu M) and inhibited the proliferation of various human cancer cell lines with averaging GI(50) about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study. (c) 2014 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | STRUCTURE-BASED OPTIMIZATION ; PROTEIN 90 INHIBITORS ; HEAT-SHOCK PROTEINS ; MOLECULAR CHAPERONE ; CANCER-THERAPY ; HEAT-SHOCK-PROTEIN-90 ; IDENTIFICATION ; DESIGN ; TARGET ; SERIES |
| 资助项目 | "Interdisciplinary Cooperation Team" Program for Science and Technology Innovation of the Chinese Academy of Sciences[00000000] ; National Natural Science Foundation of China[81072580] ; National Natural Science Foundation of China[81273368] ; National Natural Science Foundation of China[21272246] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2014ZX09507-002] ; China Marine Commonweal Research Project[201005022-5] ; National Science and Technology Major Project of the Ministry of Science and Technology of China[2012ZX09301001-007] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000363431300068 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276828]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物化学研究室 药理学第一研究室 |
| 通讯作者 | Xu, Yechun |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai 201204, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 5.Ocean Univ China, Sch Med & Pharm, Dept Pharmacol & Glycobiol, Qingdao 266003, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Danqi,Shen, Aijun,Li, Jian,et al. Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2014,87:765-781. |
| APA | Chen, Danqi.,Shen, Aijun.,Li, Jian.,Shi, Feng.,Chen, Wuyan.,...&Shen, Jingkang.(2014).Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,87,765-781. |
| MLA | Chen, Danqi,et al."Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 87(2014):765-781. |
入库方式： OAI收割
来源：上海药物研究所
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