title: Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway.
abstract: 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 μM. 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.
authors.affiliation: Center for Systems Biology, Soochow University , Suzhou 215006, China ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Dengyou
authors.initials: D
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Ruihan
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: Center for Systems Biology, Soochow University , Suzhou 215006, China ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
keywords: Anthraquinone derivatives; binding affinity with HGF; c-Met kinase inhibitors