Identification of an Aurora Kinase Inhibitor Specific for the Aurora B Isoform

doi:10.1158/0008-5472.CAN-12-2784

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

	Identification of an Aurora Kinase Inhibitor Specific for the Aurora B Isoform
	Xie, Hua3 ; Lee, Mee-Hyun 3; Zhu, Feng 3; Reddy, Kanamata 3; Peng, Cong 3; Li, Yan 3; Lim, Do Young 3; Kim, Dong Joon 3; Li, Xiang 3; Kang, Soouk 3
刊名	CANCER RESEARCH
	2013-01-15
卷号	73 期号:2 页码:716-724
ISSN号	0008-5472
DOI	10.1158/0008-5472.CAN-12-2784
文献子类	Article
英文摘要	Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. In the present study, we used a ligand docking method to explore the novel scaffold of potential Aurora B inhibitors. One thousand compounds from our in-house compound library were screened against the Aurora B structure and one compound, (E)-3-((E)-4-(benzo[d][1,3] dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one (designated herein as HOI-07) was selected for further study. HOI-07 potently inhibited in vitro Aurora B kinase activity in a dose-dependent manner, without obvious inhibition of another 49 kinases, including Aurora A. This compound suppressed Aurora B kinase activity in lung cancer cells, evidenced by the inhibition of the phosphorylation of histone H3 on Ser10 in a dose-and time-dependent manner. This inhibition resulted in apoptosis induction, G2-Marrest, polyploidy cells, and attenuation of cancer cell anchorage-independent growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of cancer cells to HOI-07. Results of an in vivo xenograft mouse study showed that HOI-07 treatment effectively suppressed the growth of A549 xenografts, without affecting the body weight of mice. The expression of phospho-histone H3, phospho-Aurora B, and Ki-67 was also suppressed in the HOI-07 treatment group. Taken together, we identified HOI-07 as a specific Aurora B inhibitor, which deserves further investigation. Cancer Res; 73(2); 716-24. (C) 2012 AACR.
资助项目	Hormel Foundation[00000000] ; NIH[R37 CA081064] ; NIH[CA120388] ; NIH[ES016548] ; NIH[CA0227501] ; National Cancer Institute[HHSN-261200533001C-NO1-CN-53301]
WOS关键词	CANCER-CELLS ; DRUG TARGET ; A KINASE ; IN-VIVO ; OVEREXPRESSION ; CHECKPOINT ; ARREST ; POLES
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000313739500030
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277767]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Dong, Zigang
作者单位	1.NCI, Bethesda, MD 20892 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Beijing, Peoples R China 3.Univ Minnesota, Hormel Inst, Austin, MN 55912 USA;
推荐引用方式 GB/T 7714	Xie, Hua,Lee, Mee-Hyun,Zhu, Feng,et al. Identification of an Aurora Kinase Inhibitor Specific for the Aurora B Isoform[J]. CANCER RESEARCH,2013,73(2):716-724.
APA	Xie, Hua.,Lee, Mee-Hyun.,Zhu, Feng.,Reddy, Kanamata.,Peng, Cong.,...&Dong, Zigang.(2013).Identification of an Aurora Kinase Inhibitor Specific for the Aurora B Isoform.CANCER RESEARCH,73(2),716-724.
MLA	Xie, Hua,et al."Identification of an Aurora Kinase Inhibitor Specific for the Aurora B Isoform".CANCER RESEARCH 73.2(2013):716-724.