Discovery of novel 1,2,4-triazolo-1,2,4-triazines with thiomethylpyridine hinge binders as potent c-Met kinase inhibitors.

Abstract

Aim: Mesenchymal-epithelial transition factor (c-Met)/HGF overactivation is involved in diverse human cancers. Materials & methods:Herein, we report the synthesis and biological evaluation of thiomethylpyridine-linked triazolotriazines as c-Met kinase inhibitors. Results: Compounds 10b and 11e were more potent than crizotinib on HepG2 cells with IC50 values of 0.74 and 0.71μM in the MTT assay, respectively. Interestingly, all of the target compounds displayed IC50 values in the range of 3.9-11.1nM in the c-Met kinase inhibition assay which were lower than the value for crizotinib (11.1nM). Conclusion: Target compound 10b can be considered as a leading drug candidate due to its lower IC50 values than crizotinib in both HGF-induced proliferation and c-Met kinase inhibition assays.