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Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N-terminal Inhibitors Without Induction of Heat Shock Response

文献类型：期刊论文

作者Liu, Peng1,2; Chen, Xiangling1,3; Zhu, Jianming2; Li, Bo1,2; Chen, Zhaoqiang1,2; Wang, Guimin1,2; Sun, Haiguo1,2; Xu, Zhijian1,2; Zhao, Zhixin3; Zhou, Chen3
刊名CHEMISTRYOPEN
出版日期2019-03-01
卷号8期号:3页码:344-353
ISSN号2191-1363
关键词autophagy Hsp72 Hsp90 inhibitor triazines antitumor activity
DOI10.1002/open.201900055
通讯作者Li, Bo(boli@simm.ac.cn) ; Xie, Chengying(xiechengying818@simm.ac.cn) ; Lou, Liguang(lglou@mail.shcnc.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn)
英文摘要Heat shock protein 90 (Hsp90) is a potential oncogenic target. However, Hsp90 inhibitors in clinical trial induce heat shock response, resulting in drug resistance and inefficiency. In this study, we designed and synthesized a series of novel triazine derivatives (A1-26, B1-13, C1-23) as Hsp90 inhibitors. Compound A14 directly bound to Hsp90 in a different manner from traditional Hsp90 inhibitors, and degraded client proteins, but did not induce the concomitant activation of Hsp72. Importantly, A14 exhibited the most potent anti-proliferation ability by inducing autophagy, with the IC50 values of 0.1 mu M and 0.4 mu M in A549 and SK-BR-3 cell lines, respectively. The in vivo study demonstrated that A14 could induce autophagy and degrade Hsp90 client proteins in tumor tissues, and exhibit anti-tumor activity in A549 lung cancer xenografts. Therefore, the compound A14 with potent antitumor activity and unique pharmacological characteristics is a novel Hsp90 inhibitor for developing anticancer agent without heat shock response.
WOS关键词HSP90 ; CHAPERONE ; BINDING ; HEAT-SHOCK-PROTEIN-90 ; OLIGOMERIZATION ; TRANSCRIPTION ; ACTIVATION ; DISCOVERY
资助项目National Key RD Plan[2016YFA0502301] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002] ; National Natural Science Foundation of China[81573350] ; National Natural Science Foundation of China[81273546] ; National Natural Science Foundation of China[81603270]
WOS研究方向Chemistry
语种英语
出版者WILEY-V C H VERLAG GMBH
WOS记录号WOS:000462770300013
源URL[http://119.78.100.183/handle/2S10ELR8/290213]  
专题中国科学院上海药物研究所
通讯作者Li, Bo; Xie, Chengying; Lou, Liguang; Zhu, Weiliang
作者单位1.Univ Chinese Acad Sci, 19 A Yuquan Rd, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Div Antitumor Pharmacol, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Peng,Chen, Xiangling,Zhu, Jianming,et al. Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N-terminal Inhibitors Without Induction of Heat Shock Response[J]. CHEMISTRYOPEN,2019,8(3):344-353.
APA Liu, Peng.,Chen, Xiangling.,Zhu, Jianming.,Li, Bo.,Chen, Zhaoqiang.,...&Zhu, Weiliang.(2019).Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N-terminal Inhibitors Without Induction of Heat Shock Response.CHEMISTRYOPEN,8(3),344-353.
MLA Liu, Peng,et al."Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N-terminal Inhibitors Without Induction of Heat Shock Response".CHEMISTRYOPEN 8.3(2019):344-353.

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来源：上海药物研究所

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