DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro

doi:10.1038/aps.2015.25

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	DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro
	Guo, Xiao-bin 2,3,4; Zhu, Wei 1; Chen, Xian-jie 1; Tong, Lin-jiang 4; Peng, Xia 4; Huang, Min4 ; Liu, Hong-chun4 ; Liu, Hong1 ; Ding, Jian4
刊名	ACTA PHARMACOLOGICA SINICA
	2015-10
卷号	36 期号:10 页码:1266-1276
关键词	DCLAK11 substituted pyridin-3-amine derivatives tyrosine kinase EGFR HER2 VEGFR2 anticancer anti-angiogenesis
ISSN号	1671-4083
DOI	10.1038/aps.2015.25
文献子类	Article
英文摘要	Aim: To investigate the molecular targets of DCLAK11, a novel compound discovered from a series of substituted pyridin-3-amine derivatives, and to characterize its anti-tumor properties in vitro. Methods: Kinase inhibition was measured by an ELISA assay. Cell viability was assessed with an SRB or a CCK8 assay. The alterations induced by kinase signaling proteins in cancer cells were detected by Western blot. Apoptosis was determined by an Annexin V-PI assay. The following assays were used to evaluate the impact on angiogenesis: wound-healing, Transwell, tube formation and microvessel outgrowth from rat aortic rings. Results: DCLAK11 was a multi-targeted kinase inhibitor that primarily inhibited the EGFR, HER2, and VEGFR2 tyrosine kinases with IC50 value of 6.5, 18, and 31 nmol/L, respectively. DCLAK11 potently inhibited the proliferation of EGFR-and HER2-driven cancer cells: its IC50 value was 12 and 22 nmol/L, respectively, in HCC827 and HCC4006 cells with EGFR exon deletions, and 19 and 81 nmol/L, respectively, in NCI-N87 and BT474 cells with HER2 amplification. Consistently, DCLAK11 blocked the EGFR and HER2 signaling in cancer cells with either an EGFR or a HER2 aberration. Furthermore, DCLAK11 effectively induced EGFR/HER2-driven cell apoptosis. Moreover, DCLAK11 exhibited anti-angiogenic activity, as shown by its inhibitory effect on the proliferation, migration and tube formation of human umbilical vascular endothelial cells and the microvessel outgrowth of rat aortic rings. Conclusions: DCLAK11 is a multi-targeted kinase inhibitor with remarkable potency against tyrosine kinases EGFR, HER2 and VEGFR2, which confirms its potent anti-cancer activity in EGFR-and HER2-addicted cancers and its anti-angiogenic activity.
资助项目	National Natural Science Foundation of China for Innovation Research Group[81321092] ; National Marine "863" project[2013AA092902] ; National Natural Science Foundation of China[91229204]
WOS关键词	ENDOTHELIAL GROWTH-FACTOR ; FACTOR RECEPTOR ; CANCER-THERAPY ; MONOCLONAL-ANTIBODY ; GENE AMPLIFICATION ; TUMOR ANGIOGENESIS ; GASTRIC-CANCER ; LUNG-CANCER ; COMBINATION ; CELLS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5531936
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000362459200013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276386]
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	Ding, Jian
作者单位	1.CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Cent S Univ, Xiangya Hosp, Dept Clin Pharmacol, Changsha 410078, Hunan, Peoples R China; 3.Cent S Univ, Inst Clin Pharmacol, Changsha 410078, Hunan, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Guo, Xiao-bin,Zhu, Wei,Chen, Xian-jie,et al. DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro[J]. ACTA PHARMACOLOGICA SINICA,2015,36(10):1266-1276.
APA	Guo, Xiao-bin.,Zhu, Wei.,Chen, Xian-jie.,Tong, Lin-jiang.,Peng, Xia.,...&Ding, Jian.(2015).DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro.ACTA PHARMACOLOGICA SINICA,36(10),1266-1276.
MLA	Guo, Xiao-bin,et al."DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro".ACTA PHARMACOLOGICA SINICA 36.10(2015):1266-1276.