期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 10, 期 2, 页码 421-430出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c1ob06186k
关键词
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资金
- National Natural Science Foundation of China [20972174, 81025017, 30725046, 91029704, 21021063]
- State Key Program of Basic Research of China [2009CB918502]
- Shanghai Committee of Science and Technology [10410703900]
- Chinese Academy of Sciences [XDA01040305]
- Guangdong ST Dept. [2010A030100006]
- Program of Shanghai Subject Chief Scientist [10XD1405100]
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 IC50 values mostly less than 10 mu M. 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 (IC50 = 0.46 mu M) 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.
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