Exploration of novel pyrrolo[2,1- f ][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2

摘要

c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50values ranged from 1.2 to 24.6?nM, especially27a. In-depth studies demonstrated27ahas great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50of 2.3?±?0.1?nM and 5.0?±?0.5?nM). Furthermore, it also showed the highest anticancer activity with IC50of 0.71?±?0.16?nM (better than the positive compound) against BaF3-TPR-Met and 37.4?±?0.311?nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated27ahas favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that27awas a potential candidate for cancer therapy deserving further study.