DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp9O-Cdc37 interaction

doi:10.1016/j.canlet.2018.07.012

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp9O-Cdc37 interaction
	Chen, Xiangling 1,2; Liu, Peng 1,2; Wang, Quanren 1; Li, Yun 1; Fu, Li 1; Fu, Haoyu 1; Zhu, Jianming 1; Chen, Zhaoqiang 1,2; Zhu, Weiliang1,2 ; Xie, Chengying1,2
刊名	CANCER LETTERS
	2018
卷号	434 页码:70-80
关键词	Cdc37 DCZ3112 Geldanamycin Hsp90 HER2-positive breast cancer
ISSN号	0304-3835
DOI	10.1016/j.canlet.2018.07.012
文献子类	Article
英文摘要	Hsp90 regulates the stability of oncoproteins important in tumor development and progression, and represents a potential therapeutic target. However, all Hsp90 inhibitors currently in clinical trials target Hsp90 ATPase activity and exhibit low selectivity and high toxicity. In this study, we discovered a new Hsp90 inhibitor, DCZ3112, with a novel mechanism of action. DCZ3112 directly bound to the N-terminal domain of Hsp90 and inhibited Hsp9O-Cdc37 interaction without inhibiting ATPase activity. DCZ3112 inhibited the proliferation predominantly in HER2-positive breast cancer cells, including those resistant to the classical Hsp90 inhibitor geldanamycin, which mainly targets ATPase. DCZ3112 produced synergistic in vitro activity in inhibiting cell proliferation, inducing G(1)-phase arrest and apoptosis, and reducing AKT and ERK phosphorylation. Consistent with this, DCZ3112 alone inhibited the growth of HER2-positive BT-474 xenografts, and exhibited enhanced antitumor activity when combined with the anti-HER2 antibody trastuzumab. Importantly, DCZ3112 also significantly inhibited the growth of trastuzumab-resistant BT-474 cells, and combined treatment retained synergistic antitumor activity. Thus, our findings show that disrupting Hsp9O-Cdc37 interaction may represent a promising strategy against HER2-positive breast cancer, especially those with acquired resistance to trastuzumab.
资助项目	National Natural Science Foundation of China[81273546] ; Shanghai Science and Technology Committee[18DZ2293200]
WOS关键词	PROTEIN 90 INHIBITORS ; 1ST-LINE TREATMENT ; TRASTUZUMAB ; COMPLEX ; GROWTH ; CELLS ; ACTIVATION ; EXPRESSION ; RESISTANCE ; DOCETAXEL
WOS研究方向	Oncology
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000444666500007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272296]
专题	药物发现与设计中心药理学第一研究室
通讯作者	Zhu, Weiliang; Xie, Chengying; Lou, Liguang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Chen, Xiangling,Liu, Peng,Wang, Quanren,et al. DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp9O-Cdc37 interaction[J]. CANCER LETTERS,2018,434:70-80.
APA	Chen, Xiangling.,Liu, Peng.,Wang, Quanren.,Li, Yun.,Fu, Li.,...&Lou, Liguang.(2018).DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp9O-Cdc37 interaction.CANCER LETTERS,434,70-80.
MLA	Chen, Xiangling,et al."DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp9O-Cdc37 interaction".CANCER LETTERS 434(2018):70-80.