Novel TIE-2 inhibitor BAY-826 displays in vivo efficacy in experimental syngeneic murine glioma models

J Neurochem. 2017 Jan;140(1):170-182. doi: 10.1111/jnc.13877. Epub 2016 Dec 12.


Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models (SMA-497 and SMA-540) and there was a significant survival benefit in one model (SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model (SMA-497), but provided synergistic prolongation of survival in another (SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.

Keywords: BAY-826; TIE-2 inhibition; glioma; irradiation; syngeneic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / enzymology*
  • Cell Line, Tumor
  • Disease Models, Animal*
  • Female
  • Glioma / drug therapy
  • Glioma / enzymology*
  • Isografts
  • Mice
  • Mice, Inbred C57BL
  • Receptor, TIE-2 / antagonists & inhibitors*
  • Receptor, TIE-2 / metabolism*
  • Treatment Outcome
  • Tumor Burden


  • Antineoplastic Agents
  • Receptor, TIE-2
  • Tek protein, mouse