Discovery of Novel 1,2,4-triazolo-1,2,4-triazines with Thiomethylpyridine Hinge Binders as Potent c-Met Kinase Inhibitors

Abstract

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