2. Academic Validation
  3. Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach

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.
Shangying Chen 1,  Chu Qin 1,  Jia En Sin 1,  Xuan Yang 1,  Lin Tao 1,  Xian Zeng 1,  Peng Zhang 1,  Chun Mei Gao 2,  Yu Yang Jiang 2,  Cheng Zhang 3,  Yu Zong Chen 1,  Wai Keung Chui 1
Affiliations

Affiliations

  • 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.
PMID: 27995811 DOI: 10.4155/fmc-2016-0162
Abstract

Aim: Simultaneous inhibition of VEGFR2/KDR/Flk-1 and Src may enhance the efficacy of VEGFR2-targeted Cancer therapeutics. Hence, development of dual inhibitors on VEGFR2/KDR/Flk-1 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/KDR/Flk-1 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/KDR/Flk-1 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.

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