CM082, a novel VEGF receptor tyrosine kinase inhibitor, can inhibit angiogenesis in vitro and in vivo

Microvasc Res. 2021 Jul:136:104146. doi: 10.1016/j.mvr.2021.104146. Epub 2021 Feb 19.

Abstract

The goal of this study was to evaluate the effects of CM082, a novel vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor, on human umbilical vein endothelial cells (HUVECs), and oxygen-induced retinopathy (OIR) mice. HUVECs were stimulated with rHuVEGF165 and then treated with CM082 to assess the antiangiogenic effects of CM082; subsequently, proliferation, wound-healing migration, Transwell invasion, tube formation assays, and Western blotting were performed in vitro. Retinal neovascularization tufts, avascular area, and TUNEL assays were estimated for OIR mice after intraperitoneal injection with CM082. CM082 significantly inhibited proliferation, migration, invasion, and tube formation induced by stimulation of HUVECs with rHuVEGF165; this inhibitory effect was mediated by blocking VEGFR2 activation. CM082 significantly inhibited retinal neovascularization and avascular area and did not increase apoptosis in the retina of OIR mice. The findings demonstrated that CM082 exhibits highly antiangiogenic effects in HUVECs and OIR mice. Thus, it may serve as an alternative treatment for neovascular eye disease in the future.

Keywords: CM082; Human umbilical vein endothelial cells (HUVEC); Oxygen-induced retinopathy (OIR); Vascular endothelial growth factor (VEGF).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / enzymology
  • Humans
  • Hyperoxia / complications
  • Indoles / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / pharmacology*
  • Pyrrolidines / pharmacology*
  • Retinal Neovascularization / enzymology
  • Retinal Neovascularization / etiology
  • Retinal Neovascularization / pathology
  • Retinal Neovascularization / prevention & control*
  • Retinopathy of Prematurity / drug therapy*
  • Retinopathy of Prematurity / enzymology
  • Retinopathy of Prematurity / etiology
  • Retinopathy of Prematurity / pathology
  • Signal Transduction
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrroles
  • Pyrrolidines
  • KDR protein, human
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2
  • vorolanib