Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors.
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.
['Zhang|Dengyou|D|', 'Zhang|Xiaowei|X|', 'Ai|Jing|J|', 'Zhai|Yun|Y|', 'Liang|Zhongjie|Z|', 'Wang|Ying|Y|', 'Chen|Yi|Y|', 'Li|Chunpu|C|', 'Zhao|Fei|F|', 'Jiang|Hualiang|H|', 'Geng|Meiyu|M|', 'Luo|Cheng|C|', 'Liu|Hong|H|']
D000818:Animals D000970:Antineoplastic Agents D001665:Binding Sites D059447:Cell Cycle Checkpoints D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D004285:Dogs D019008:Drug Resistance, Neoplasm 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 D010766:Phosphorylation D047428:Protein Kinase Inhibitors D017434:Protein Structure, Tertiary D019859:Proto-Oncogene Proteins c-met D011725:Pyridines D051381:Rats D015398:Signal Transduction D013329:Structure-Activity Relationship D013449:Sulfonamides D014183:Transplantation, Heterologous
2-Amino-5-aryl-3-benzylthiopyridine c-Met Receptor tyrosine kinase