Discovery of novel anti-angiogenesis agents. Part 10: Multi-target inhibitors of VEGFR-2, Tie-2 and EphB4 incorporated with 1,2,3-triazol

  • Eur J Med Chem. 2019 Feb 1:163:1-9. doi: 10.1016/j.ejmech.2018.11.042.
Xiaoyan Pan  1 ,  Liyuan Liang  1 ,  Ru Si  1 ,  Jin Wang  1 ,  Qingqing Zhang  1 ,  Huaxin Zhou  1 ,  Lin Zhang  1 ,  Jie Zhang  2
Affiliations
  • 1. School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
  • 2. School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China. Electronic address: [email protected].
PMID: 30503935 DOI: 10.1016/j.ejmech.2018.11.042
Abstract

VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we developed a series of pyridines incorporated with 1,2,3-triazole as multi-target inhibitors based on the crystal structure alignment of the kinase domain of angiogenic RTKs. Biological results indicated that these multi-target inhibitors displayed considerable potential as novel anti-angiogenic agents. Among them, compound BD7 exhibited the most potent inhibition against the three RTKs simultaneously, and good activity on inhibiting viability of human umbilical endothelial cells. Therefore, 1,2,3-triazole could serve as a promising DFG binding group for multi-target inhibitors of VEGFR-2, TIE-2 and EphB4 bearing pyridine as hinge binding group.

Keywords
1,2,3-Triazole; Anti-angiogenic agents; DFG-binding group; Multi-target; Triple RTK inhibitors.