title: Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors.
abstract: The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 μM) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases.
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No. 152, Luoyu Road, Hongshan District, Wuhan 430079, PR China.
authors.forename: Nengfang
authors.initials: N
authors.lastname: She
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No. 152, Luoyu Road, Hongshan District, Wuhan 430079, PR China.
authors.forename: Linsheng
authors.initials: L
authors.lastname: Zhuo
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No. 152, Luoyu Road, Hongshan District, Wuhan 430079, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No. 152, Luoyu Road, Hongshan District, Wuhan 430079, PR China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, Jiangsu Simcere Pharmaceutical Co. Ltd, Nanjing 210042, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, Jiangsu Simcere Pharmaceutical Co. Ltd, Nanjing 210042, PR China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Ming
authors.affiliation: Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, Jiangsu Simcere Pharmaceutical Co. Ltd, Nanjing 210042, PR China.
authors.forename: Xinge
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, Jiangsu Simcere Pharmaceutical Co. Ltd, Nanjing 210042, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cong
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No. 152, Luoyu Road, Hongshan District, Wuhan 430079, PR China; State Key Laboratory of Agricultural Microbiology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China. Electronic address: weihuangwuhan@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; 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; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D019859:Proto-Oncogene Proteins c-met
keywords: Kinase inhibitor; MET; Pyridone; Selectivity