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

文献类型：期刊论文

作者Chen, Xiangling1,2; Liu, Peng1,2; Wang, Quanren1; Li, Yun1; Fu, Li1; Fu, Haoyu1; Zhu, Jianming1; Chen, Zhaoqiang1,2; Zhu, Weiliang1,2; Xie, Chengying1,2
刊名CANCER LETTERS
出版日期2018
卷号434页码:70-80
关键词Cdc37 DCZ3112 Geldanamycin Hsp90 HER2-positive breast cancer
ISSN号0304-3835
DOI10.1016/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.
WOS关键词PROTEIN 90 INHIBITORS ; 1ST-LINE TREATMENT ; TRASTUZUMAB ; COMPLEX ; GROWTH ; CELLS ; ACTIVATION ; EXPRESSION ; RESISTANCE ; DOCETAXEL
资助项目National Natural Science Foundation of China[81273546] ; Shanghai Science and Technology Committee[18DZ2293200]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000444666500007
出版者ELSEVIER IRELAND LTD
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.

入库方式： OAI收割

来源：上海药物研究所

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