title: Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor.
abstract: c-Met/HGF overexpression has been detected in many human malignancies including tumors which are resistant to anticancer therapy. Disrupting the aberrant c-Met/HGF axis has enjoyed significant progress in both preclinical and clinical antitumor campaign. To eliminate the OCH2-related metabolic deficiency of our previously reported triazolotriazine 2, we synthesized a series of CH2-/CF2-linked triazolotriazines and assessed their c-Met activities, leading to the highly potent compound 23 with IC50 values of 0.24 nM of enzymatic activity in c-Met and 0.85 nM of cellular activity in EBC-1 cancer cell line, as well as with complete tumor regression in EBC-1 xenograft mice model at dose of 25 mg/kg via oral administration. Based on its potent anti-proliferative activities and favorable pharmacokinetic properties, 23 has been selected as a drug candidate for preclinical investigation.
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Zhan
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Qiufeng
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Yinchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Shanyan
authors.initials: S
authors.lastname: Yao
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: ycxu@simm.ac.cn.
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: jai@simm.ac.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: whduan@simm.ac.cn.
authors.forename: Wenhu
authors.initials: W
authors.lastname: Duan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011804:Quinolines; D014227:Triazines; D019859:Proto-Oncogene Proteins c-met
keywords: Antitumor; Kinase inhibitor; Triazolotriazines; c-Met