title: Discovering potent inhibitors against c-Met kinase: molecular design, organic synthesis and bioassay.
abstract: The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. The discovery of small molecule inhibitors is of special interest in the blockade of the c-Met kinase pathway. Here, we initiated our study from compound 1a, a novel inhibitor against c-Met kinase. A substructure similarity search against the SPECS database and chemical synthesis methods were performed to obtain a series of pyrazolidine-3,5-dione derivatives. Through the enzyme-based assay against c-Met kinase, 4 compounds (1c, 1e, 1m and 1o) showed potential inhibitory activity, with IC(50) values mostly less than 10 μM. Based on the structure-activity relationship (SAR) and binding mode analysis, a focused combinatorial library was designed by the LD1.0 program. Taking into account ADMET properties and synthesis accessibility, seven candidate compounds (5a-g) were successfully synthesized. The activity of the most potent compounds 5b (IC(50) = 0.46 μM) was 20 fold higher than that of the lead 1a. Taken together, our findings identified the pyrazolidine-3,5-dione derivatives as potent inhibitors against c-Met kinase and demonstrated the efficiency of the strategy in the development of small molecules against c-Met kinase.
authors: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Zhongjie
authors: Z
authors: Liang
authors: Xiao
authors: X
authors: Ding
authors: Jing
authors: J
authors: Ai
authors: Xiangqian
authors: X
authors: Kong
authors: Limin
authors: L
authors: Chen
authors: Liang
authors: L
authors: Chen
authors: Cheng
authors: C
authors: Luo
authors: Meiyu
authors: M
authors: Geng
authors: Hong
authors: H
authors: Liu
authors: Kaixian
authors: K
authors: Chen
authors: Hualiang
authors: H
authors: Jiang
mesh_terms: D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; 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; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met