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: Zhongjie Liang, Xiao Ding, Jing Ai, Xiangqian Kong, Limin Chen, Liang Chen, Cheng Luo, Meiyu Geng, Hong Liu, Kaixian Chen, Hualiang Jiang
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 10 Issue 2 Pg. 421-30 (Jan 14 2012) ISSN: 1477-0539 [Electronic] England
• PMID: 22108637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-met

Topics

• Combinatorial Chemistry Techniques
• Drug Discovery
• Enzyme-Linked Immunosorbent Assay
• Models, Molecular
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship