Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors

doi:10.1016/j.ejmech.2014.09.065

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	Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors
	Chen, Danqi1 ; Shen, Aijun2 ; Li, Jian 3; Shi, Feng 1; Chen, Wuyan 4; Ren, Jing 1; Li, Hongchun 2; Xu, Yechun4 ; Wang, Xin1 ; Yang, Xinying 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	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.
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关键词	STRUCTURE-BASED OPTIMIZATION ; PROTEIN 90 INHIBITORS ; HEAT-SHOCK PROTEINS ; MOLECULAR CHAPERONE ; CANCER-THERAPY ; HEAT-SHOCK-PROTEIN-90 ; IDENTIFICATION ; DESIGN ; TARGET ; SERIES
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:000363431300068
内容类型	期刊论文
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.