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

doi:10.1111/cas.12934

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	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
	Wang, Wenqian; Liu, Yang; Zhao, Zhixin; Xie, Chengying; Xu, Yongping; Hu, Youhong; Quan, Haitian; Lou, Liguang
刊名	CANCER SCIENCE
	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
DOI	10.1111/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.
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
WOS研究方向	Oncology
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000378715100009
内容类型	期刊论文
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.