Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway
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- 作者：Zhongjie Liang ; Jing Ai ; Xiao Ding ; Xia Peng ; Dengyou Zhang ; Ruihan Zhang ; Ying Wang ; Fang Liu ; Mingyue Zheng ; Hualiang Jiang ; Hong Liu ; Meiyu Geng ; Cheng Luo
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：April 11, 2013
- 年：2013
- 卷：4
- 期：4
- 页码：408-413
- 全文大小：377K
- 年卷期：v.4,no.4(April 11, 2013)
- ISSN：1948-5875
文摘
The aberrant function of c-Met kinase signaling pathway is ubiquitously involved in a broad spectrum of human cancers; thus, a strong rationale exists for targeting the kinase pathway in cancer therapy. Via integration of computational and experimental studies, anthraquinone derivatives were identified for the first time as potent c-Met kinase inhibitors in this research. The aberrant activation of the c-Met kinase pathway results from (TPR)-Met, MET gene mutation, or amplification and a hepatocyte growth factor (HGF)/scatter factor-dependent autocrine or paracrine mechanism. However, anthraquinone derivatives exclusively suppressed c-Met phosphorylation stimulated by HGF in A549 cells, indicating that the compounds possess the ability to block the extracellular HGF-dependent pathway. A surface plasmon resonance assay revealed that the most potent compound, 2a, shows a high binding affinity for HGF with an equilibrium dissociation constant of 1.95 渭M. The dual roles of compound 2a demonstrate the potency of anthraquinone derivatives and provide a new design solution for the c-Met kinase signaling pathway.