DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro | |
Guo, Xiao-bin2,3,4; Zhu, Wei1; Chen, Xian-jie1; Tong, Lin-jiang4; Peng, Xia4; Huang, Min4![]() ![]() ![]() ![]() | |
刊名 | ACTA PHARMACOLOGICA SINICA
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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. |
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