Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach
- Future Med Chem. 2017 Jan;9(1):7-24. doi: 10.4155/fmc-2016-0162.
- 1. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
- 2. Shenzhen Kivita Innovative Drug Discovery Institute & the Key Laboratory of Chemical Biology, Guangdong Province, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong, PR China.
- 3. Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55902, USA.
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.
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