title: Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization.
abstract: Starting from our previously identified novel c-Met kinase inhibitors bearing 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations.
authors.affiliation: Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiao-De
authors.initials: XD
authors.lastname: An
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hongyan
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: Zhong-Liang
authors.initials: ZL
authors.lastname: Xu
authors.affiliation: School of Chemical Science and Technology, Yunnan University, Kunming 650091, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
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: Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China. Electronic address: yaoym@suda.edu.cn.
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: yqlong@simm.ac.cn.
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000600672:imidazo(4,5-b)pyridine; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met
keywords: Binding mode; Cyclopropane-1,1-dicarboxamide; Imidazonaphthyridinone; Imidazopyridine; Pyridone-3-carboxamide; Small molecule inhibitor; c-Met tyrosine kinase