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

Guo XB, Chen XJ, Tong LJ, Peng X, Huang M, Liu HC, Liu H, Ding J - Acta Pharmacol. Sin. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Xiangya Hospital and Institute of Clinical Pharmacology, Central South University, Changsha 410078, China.

ABSTRACT

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.

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Chemical structures of DCLAK11.
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fig1: Chemical structures of DCLAK11.

Mentions: A series of substituted pyridin-3-amine derivatives was designed and synthesized at Prof Hong Liu's Laboratory in Shanghai Institute of Materia Medica. Compound DCLAK11(chemical structure shown in Figure 1, synthetic route shown in Supplementary Scheme 1) presented promising activities in a biological screening and was selected for further evaluation. The purity of DCLAK11 was 98%. In this study, DCLAK11 was dissolved to 10 mmol/L in DMSO as a stock solution and stored at -20 °C.


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

Guo XB, Chen XJ, Tong LJ, Peng X, Huang M, Liu HC, Liu H, Ding J - Acta Pharmacol. Sin. (2015)

Chemical structures of DCLAK11.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814203&req=5

fig1: Chemical structures of DCLAK11.
Mentions: A series of substituted pyridin-3-amine derivatives was designed and synthesized at Prof Hong Liu's Laboratory in Shanghai Institute of Materia Medica. Compound DCLAK11(chemical structure shown in Figure 1, synthetic route shown in Supplementary Scheme 1) presented promising activities in a biological screening and was selected for further evaluation. The purity of DCLAK11 was 98%. In this study, DCLAK11 was dissolved to 10 mmol/L in DMSO as a stock solution and stored at -20 °C.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Xiangya Hospital and Institute of Clinical Pharmacology, Central South University, Changsha 410078, China.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus