生物活性

• 描述The Tie family of receptor tyrosine kinases plays a crucial role in the development and function of endothelial tissues. Genetic studies have revealed specific roles for the Tie receptors (Tie1 & Tie2) and their ligands (angiopoietins) in promoting the survival, maturation and functional integrity of the vasculature. Inhibition of Tie2 is expected to disrupt angiogenesis and tumor growth via inhibition of vascular modeling. Tie2 kinase-IN-1 is a reversible and selective inhibitor of Tie2 with IC50 of 0.25 μM, whose selectivity is 200-fold higher than that of p38. in vitro， Tie2 kinase inhibitor exhibits significant inhibitory effect on Tie2 auto-phosphorylation and disrupts its downstream signal transduction in a dose dependent manner in human aortic endothelial cells. In addition, Tie2 kinase inhibitor exhibits moderately suppressed the activity of Tie2 tyrosine kinase in HEL cells with IC50 of 232 nM. Matrigel mouse model of angiogenesis is adopted for in vivo study. Tie2 kinase inhibitor at doses of 25 and 50 mg/kg (i.p., b.i.d) reduces 41% and 70% of angiogenesis, respectively. In a MOPC-315 plasmacytoma xenograft model, Tie2 kinase inhibitor modestly suppresses tumor growth in nude mice in a dose-dependent manner. A phase I study is conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses of Tie2 kinase inhibitor. It is noticed that this kind of compounds could be well tolerated and has sufficient activity.

• 动物研究
  剂量	Mice: 50 mg/kg[1] (i.p.)
  给药途径	i.p.