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 0.71 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). 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.

Plain Language Summary

Graphical abstract Compound 10b was introduced as a potent c-Met kinase inhibitor with IC₅₀ of 4.6 nM and was more cytotoxic than crizotinib on HepG2 cells.

Keywords: :

• anticancer
• caspase 3/7
• c-met kinase
• synthesis
• x-ray crystallography
• [1,2,4]triazolo[4,3-b][1,2,4]triazine

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Corrigendum

Supplementary data

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Financial & competing interests disclosure

This study was related to the PhD thesis of S Dadashpour and was supported by grant number 1967, Mazandaran University of Medical Sciences, Sari, Iran. The authors thank the University of Reading for use of the Gemini diffractometer in the Chemical Analysis Facility. Enzymatic c-Met kinase assay was financially supported by National Institute for Medical Research Development (NIMAD), Iran, through grant no. 957396. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.