Discovering potent inhibitors against c-Met kinase: molecular design, organic
synthesis and bioassay

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 mM. 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 mM) 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.