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Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo

文献类型：期刊论文

作者Wang, Wenqian; Liu, Yang; Zhao, Zhixin; Xie, Chengying; Xu, Yongping; Hu, Youhong; Quan, Haitian; Lou, Liguang
刊名CANCER SCIENCE
出版日期2016-06
卷号107期号:6页码:782-790
关键词Hop Hsp90 imatinib resistance thiol oxidation Y-632
ISSN号1347-9032
DOI10.1111/cas.12934
文献子类Article
英文摘要Heat shock protein 90 (Hsp90) stabilizes a variety of proteins required for cancer cell survival and has been identified as a promising drug target for cancer treatment. To date, several Hsp90 inhibitors have entered into clinical trials, but none has been approved for cancer therapy yet. Thus, exploring new Hsp90 inhibitors with novel mechanisms of action is urgent. In the present study, we show that Y-632, a novel pyrimidine derivative, inhibited Hsp90 in a different way from the conventional Hsp90 inhibitor geldanamycin. Y-632 induced degradation of diverse Hsp90 client proteins through the ubiquitin-proteasome pathway, as geldanamycin did; however, it neither directly bound to Hsp90 nor inhibited Hsp90 ATPase activity. Y-632 inhibited Hsp90 function mainly through inducing intracellular thiol oxidation, which led to disruption of the Hsp90-Hsp70/Hsp90 organizing protein complex and further induced cell adhesion inhibition, G(0)/G(1) cell cycle arrest, and apoptosis. Moreover, Y-632 efficiently overcame imatinib resistance mediated by Bcr-Abl point mutations both in vitro and in vivo. We believe that Y-632, acting as a novel small-molecule inhibitor of the Hsp90-Hsp70/Hsp90 organizing protein complex, has great potential to be a promising Hsp90 inhibitor for cancer therapy, such as for imatinib-resistant leukemia.
WOS关键词CHRONIC MYELOID-LEUKEMIA ; SMALL-MOLECULE INHIBITORS ; BREAST-CANCER CELLS ; CLINICAL DEVELOPMENT ; POSTTRANSLATIONAL MODIFICATIONS ; PROTEASOMAL DEGRADATION ; COMPLEX-FORMATION ; MDA-MB-231 CELLS ; ANTICANCER AGENT ; TARGETING HSP90
资助项目National Natural Science Foundation of China[Y201181042] ; National Natural Science Foundation of China[81273546] ; Shanghai Science and Technology Committee[14DZ2294100] ; Ministry of Science and Technology of China, National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09102008] ; Ministry of Science and Technology of China, National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09402102-001]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000378715100009
出版者WILEY-BLACKWELL
源URL[http://119.78.100.183/handle/2S10ELR8/276014]  
专题药理学第一研究室
通讯作者Quan, Haitian
作者单位Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Wenqian,Liu, Yang,Zhao, Zhixin,et al. Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo[J]. CANCER SCIENCE,2016,107(6):782-790.
APA Wang, Wenqian.,Liu, Yang.,Zhao, Zhixin.,Xie, Chengying.,Xu, Yongping.,...&Lou, Liguang.(2016).Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo.CANCER SCIENCE,107(6),782-790.
MLA Wang, Wenqian,et al."Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo".CANCER SCIENCE 107.6(2016):782-790.

入库方式： OAI收割

来源：上海药物研究所

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