AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo

doi:10.1371/journal.pone.0021487

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	AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo
	Xie, Hua1 ; Lin, Liping 1; Tong, Linjiang 1; Jiang, Yong 2; Zheng, Mingyue3 ; Chen, Zhuo 1; Jiang, Xiaoyan 5; Zhang, Xiaowei 1; Ren, Xiaowei 2; Qu, Wenchao 5
刊名	PLOS ONE
	2011-07-18
卷号	6 期号:7
ISSN号	1932-6203
DOI	10.1371/journal.pone.0021487
文献子类	Article
英文摘要	Despite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studies have provided compelling evidence that irreversible ErbB inhibitors have the potential to override this resistance. Here, we found that AST1306, a novel anilino-quinazoline compound, inhibited the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. Importantly, AST1306 functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that AST1306 inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to AST1306, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to AST1306 antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to AST1306. In vivo, AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(ne)u transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of AST1306 in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (>= 24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish AST1306 as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells.
资助项目	Key New Drug Creation and Manufacturing Program[2009ZX09103-001] ; Key New Drug Creation and Manufacturing Program[2009ZX09103-102] ; National Natural Science Foundation of China[81021062] ; Shanghai Committee of Science and Technology[10431902600] ; Shanghai Key Lab of Chemical Biology[SKLCB-2008-03]
WOS关键词	TYROSINE KINASE INHIBITOR ; CELL LUNG-CANCER ; ADVANCED SOLID TUMORS ; ACQUIRED-RESISTANCE ; PHASE-I ; T790M MUTATION ; ERBB RECEPTORS ; EGF RECEPTOR ; GEFITINIB ; HER2
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000292812400009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278471]
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	Xie, Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 200031, Peoples R China; 2.Shanghai Allist Pharmaceut, Shanghai, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 5.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Xie, Hua,Lin, Liping,Tong, Linjiang,et al. AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo[J]. PLOS ONE,2011,6(7).
APA	Xie, Hua.,Lin, Liping.,Tong, Linjiang.,Jiang, Yong.,Zheng, Mingyue.,...&Ding, Jian.(2011).AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo.PLOS ONE,6(7).
MLA	Xie, Hua,et al."AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo".PLOS ONE 6.7(2011).