A novel 2‐aminobenzimidazole‐based compound Jzu 17 exhibits anti‐angiogenesis effects by targeting VEGFR‐2 signalling

Abstract

Background and Purpose Recent development in drug discovery have shown benzimidazole to be an important pharmacophore,. Benzimidazole derivatives exhibit broad‐spectrum pharmacological properties including anti‐microbial, anti‐diabetic and anti‐tumour activity. However, whether benzimidazole derivatives are effective in suppressing angiogenesis and its underlying mechanisms remain incompletely understood. In this study, we aim to characterize the anti‐angiogenic mechanisms of a novel 2‐aminobenzimidazole‐based compound, Jzu 17, in an effort to develop novel angiogenesis inhibitor. Experimental Approach Effects of Jzu 17 on endothelial cell proliferation, migration, invasion, and activation of signalling molecules induced by VEGF‐A, were analysed by immunoblotting, MTT, BrdU, migration, and invasion assays. We performed tube formation assay, aorta ring sprouting assay, matrigel plug assay, and a mouse model of metastasis to evaluate ex vivo and in vivo anti‐angiogenic effects of Jzu 17. Key Results Jzu 17 inhibited VEGF‐A‐induced cell proliferation, migration, invasion, and endothelial tube formation of HUVECs. Jzu 17 suppressed VEGF‐A‐induced microvessel sprouting ex vivo and attenuated VEGF‐A‐ or tumour cell‐induced neovascularization in vivo. Jzu 17 also reduced B16F10 melanoma lung metastasis. In addition, Jzu 17 inhibited the phosphorylation of VEGFR‐2 and its downstream signalling molecules in VEGF‐A‐stimulated HUVECs. Results from computer modelling further showed that Jzu 17 binds to VEGFR‐2 with high affinity. Conclusions and Implications Jzu 17 may inhibit endothelial remodelling and suppress angiogenesis through targeting VEGF‐A‐VEGFR‐2 signalling. These results also suggest Jzu 17 as a potential lead compound and warrant the clinical development of similar agents in the treatment of cancer and angiogenesis‐related diseases.

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“…Aorta ring sprouting assay was performed as described previously 32 . Aortic rings isolated from 6- to 8-week-old male Sprague–Dawley rats, then cleaned off periadventitial fat and cut into 1.5 mm size.…”

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“…Target compound 18 also found to reduce lung metastasis of B16F10 melanoma cells in mice models. Molecular docking studies of target compound showed strong binding with in the active site of VEGFR-2 by forming hydrogen bond between nitrogen of benzimidazole with amino acid residue His1026 [63].…”

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