Design, synthesis, and biological evaluation of thiazole/thiadiazole carboxamide scaffold-based derivatives as potential c-Met kinase inhibitors for cancer treatment

As part of our continuous efforts to discover novel c-Met inhibitors as antitumor agents, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesised, and evaluated for the in vitro activity against c-Met and four human cancer cell lines. After five cycles of optimisation on structure-activity relationship, compound 51am was found to be the most promising inhibitor in both biochemical and cellular assays. Moreover, 51am exhibited potency against several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in the cell and cell-free systems. It also exhibited a good pharmacokinetic profile in BALB/c mice. Furthermore, the binding mode of 51am with both c-Met and VEGFR-2 provided novel insights for the discovery of selective c-Met inhibitors. Taken together, these results indicate that 51am could be an antitumor candidate meriting further development.

Automated summary

In this study, four series of thiazole/thiadiazole carboxamide-derived analogues were designed, synthesized, and evaluated as novel c-Met inhibitors for antitumor therapy. Compound 51am was identified as the most promising inhibitor with significant activity against c-Met and several c-Met mutants. Mechanistically, 51am not only induced cell cycle arrest and apoptosis in MKN-45 cells but also inhibited c-Met phosphorylation in both cell and cell-free systems. In addition, 51am showed good pharmacokinetic properties in mice and its binding mode with c-Met and VEGFR-2 provided new insights for the discovery of selective c-Met inhibitors. These findings suggest that 51am has the potential to be further developed as an antitumor candidate.