title: O-linked triazolotriazines: potent and selective c-Met inhibitors.
abstract: The HGF/c-Met signaling pathway mediates a variety of important biological activities, but dysregulation of the pathway is also closely associated with poor prognosis in a wide range of human cancers. c-Met is considered to be among the most promising therapeutic targets for anticancer drug discovery. Herein we report the discovery of a series of O-linked triazolotriazines that show sub-nanomolar inhibition of c-Met activity. Among these new compounds, 6 a exhibits high c-Met inhibitory potency in both enzymatic and cellular assays with great selectivity.
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Zhan
authors.forename: Yongcong
authors.initials: Y
authors.lastname: Lv
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Desheng
authors.initials: D
authors.lastname: Mei
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Wenhu
authors.initials: W
authors.lastname: Duan
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D014227:Triazines; D014230:Triazoles; D019859:Proto-Oncogene Proteins c-met