Discovery of novel anti-angiogenesis agents. Part 11: Development of PROTACs based on active molecules with potency of promoting vascular normalization

Eur J Med Chem. 2020 Nov 1:205:112654. doi: 10.1016/j.ejmech.2020.112654. Epub 2020 Jul 23.

Abstract

Our recent investigation is focused on the discovery of anti-angiogenesis agents. Vascular normalization induced by anti-angiogenic agent appears to be a promising strategy. We have developed novel angiogenesis inhibitors with potency of promoting vascular normalization. Herein, we reported the design, synthesis and preliminary evaluation of proteolysis-targeting chimera (PROTACs) based on the previously developed anti-angiogenesis agents. Two PROTACs exhibited potent VEGFR-2 inhibition and anti-proliferative activity against HUVECs. Moreover, they were capable of reducing protein levels of VEGFR-2 in EA.hy926 cells without significant cytotoxicity against HEK293 cells. The novel PROTACs could be used to normalize the abnormal vessels, resulting in efficient delivery of drugs.

Keywords: Active molecules; Anti-angiogenesis agents; PROTACs; Vascular normalization.

MeSH terms

  • Angiogenesis Inhibitors / chemistry*
  • Angiogenesis Inhibitors / pharmacology*
  • Cell Proliferation / drug effects
  • Drug Design*
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Proteolysis / drug effects*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

  • Angiogenesis Inhibitors
  • Vascular Endothelial Growth Factor Receptor-2