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

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...

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Vydané v:	Acta pharmacologica Sinica Ročník 36; číslo 10; s. 1266 - 1276
Hlavní autori:	Guo, Xiao-bin, Chen, Xian-jie, Tong, Lin-jiang, Peng, Xia, Huang, Min, Liu, Hong-chun, Liu, Hong, Ding, Jian
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 01.10.2015 Nature Publishing Group
Predmet:	Angiogenesis Inhibitors - chemistry Angiogenesis Inhibitors - pharmacology Animals Apoptosis - drug effects Biomedical and Life Sciences Biomedicine Cell Line, Tumor Cell Proliferation - drug effects Human Umbilical Vein Endothelial Cells Humans Immunology Internal Medicine Male Medical Microbiology Neoplasms - drug therapy Neoplasms - metabolism Neoplasms - pathology Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology Original original-article Pharmacology/Toxicology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyridines - chemistry Pyridines - pharmacology Rats, Sprague-Dawley Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - metabolism Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - metabolism Signal Transduction - drug effects Vaccine Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - metabolism 体外实验体外抗肿瘤化合物抗血管生成衍生物酪氨酸激酶抑制剂 substituted pyridin-3-amine derivatives VEGFR2 tyrosine kinase anti-angiogenesis HER2 DCLAK11 EGFR anticancer
ISSN:	1671-4083, 1745-7254, 1745-7254
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Shrnutí:	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.Conclusion： 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.
Bibliografia:	DCLAK11; substituted pyridin-3-amine derivatives; tyrosine kinase; EGFR; HER2; VEGFR2; anticancer; anti-angiogenesis 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.Conclusion： 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. 31-1347/R ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23
ISSN:	1671-4083 1745-7254 1745-7254
DOI:	10.1038/aps.2015.25