Jingwei Liang, Xinyang Li, Su Yang, Xin He, Mingyang Wang and Fanhao Meng* Pages 734 - 740 ( 7 )
Backgound: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. Type I inhibitors constitute the major ATP-competitive inhibitors and recognize mainly the active conformation of VEGFR-2. Meanwhile, type II inhibitors recognize the inactive DFG (Asp- Phe-Gly)-out conformation of VEGFR-2, which was a more promising approach for drug intervention.
Methods: According to the lead compound of uracil skeleton, being screened out by structure-based virtual screening, a series of uracil derivatives were designed and synthesized. Results: The inhibitory activities were investigated against VEGFR-2 kinase in vitro. The results turned out that series A performed moderate inhibitory activities, especially compound A4 exhibited the most potent inhibitory activity (IC50=0.029 µM).
Conclusion: The lead compound was screened out by structure-based pharmacophore models, then two series of uracil derivatives were synthesized according to it and evaluated for their inhibitory activities against VEGFR-2. In this study, not only a potential inhibitor has been discovered, it also demonstrates the feasibility of structure-based virtual screening method for drug discovery.
VEGFR-2 inhibitor, uracil, virtual screening, Acyl aromatic hydrazine, cancer angiogenesis, ATP-competitive inhibitors.
School of Pharmacy, China Medical University, Liaoning 110122, Shenyang, School of Pharmacy, China Medical University, Liaoning 110122, Shenyang, School of Pharmacy, China Medical University, Liaoning 110122, Shenyang, School of Pharmacy, China Medical University, Liaoning 110122, Shenyang, School of Pharmacy, China Medical University, Liaoning 110122, Shenyang, School of Pharmacy, China Medical University, Liaoning 110122, Shenyang