Aim: Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2-targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments.
Materials & methods: A multistep virtual screening protocol, comprising ligand-based support vector machines method, drug-likeness rules filter and structure-based molecular docking, was developed and employed to identify dual inhibitors of VEGFR2 and Src from a large commercial chemical library. Kinase inhibitory assays and cell viability assays were then used for experimental validation.
Results: A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound 3c belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src.
Conclusion: This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents.
Keywords: 2-amino-3-cyanopyridines; Src; Surflex–Dock; VEGFR2; cancer; combinatorial support vector machines; drug discovery; molecular docking; multikinase inhibitors; virtual screening.