title: Discovery of Potent c-MET Inhibitors with New Scaffold Having Different Quinazoline, Pyridine and Tetrahydro-Pyridothienopyrimidine Headgroups.
abstract: Cellular mesenchymal-epithelial transition factor (c-MET) is closely linked to human malignancies, which makes it an important target for treatment of cancer. In this study, a series of 3-methoxy-N-phenylbenzamide derivatives, N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl) benzamide derivatives and N¹-(3-fluoro-4-methoxyphenyl)-N³-(4-fluorophenyl) malonamide derivatives were designed and synthesized, some of them were identified as c-MET inhibitors. Among these compounds with new scaffolds having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine head groups, compound 11c, 11i, 13b, 13h exhibited both potent inhibitory activities against c-MET and high anticancer activity against tested cancer cell lines in vitro. In addition, kinase selectivity assay further demonstrated that both 13b and 13h are potent and selective c-MET inhibitors. Molecular docking supported that they bound well to c-MET and VEGFR2, which demonstrates that they are potential c-MET RTK inhibitors for cancer therapy.
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. j1074736705@163.com.
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. xjzk1984@163.com.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. gsy19900922@163.com.
authors.forename: Suyu
authors.initials: S
authors.lastname: Gao
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. redticky@126.com.
authors.forename: Guihua
authors.initials: G
authors.lastname: Wang
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. 13504051049@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. profwjh@126.com.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. syzyclx@163.com.
authors.forename: Lixia
authors.initials: L
authors.lastname: Chen
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry*; D011799:Quinazolines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D019859:Proto-Oncogene Proteins c-met
keywords: MET inhibitor; cancer therapy; pyridine; quinazoline; tetrahydro-pyridothienopyrimidine