title: Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors.
abstract: A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC50 up to 7.7nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71μM) and c-Met activation-mediated cell metastasis. At a dose of 100mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.
authors.affiliation: State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
authors.forename: Dengyou
authors.initials: D
authors.lastname: Zhang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhai
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Chunpu
authors.initials: C
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D019859:Proto-Oncogene Proteins c-met; C023666:pyridine
keywords: 2-Amino-5-aryl-3-benzylthiopyridine; Receptor tyrosine kinase; c-Met