Background:

IC50: A reversible and selective inhibitor of Tie2 with IC50 of 0.25 M, whose selectivity is 200-fold higher than that of p38.

Genetic studies have identified the crucial roles of Tie receptors (Tie1 & Tie2) in the development and function of endothelial tissues, including promoting the survival, maturation and functional integrity of the vasculature. Tie2 kinase inhibitor is suggested to block vascular construction via suppressing Tie2, and in this way it is expected to disrupt tumor growth and angiogenesis. [1]

In vitro: Tie2 kinase inhibitor exhibited significant inhibitory effect on Tie2 auto-phosphorylation and disrupted 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. [2, 3]

In vivo: Matrigel mouse model of angiogenesis was adopted for in vivo study. Tie2 kinase inhibitor at doses of 25 and 50 mg/kg (i.p., b.i.d) reduced 41% and 70% of angiogenesis, respectively. In a MOPC-315 plasmacytoma xenograft model, Tie2 kinase inhibitor modestly suppressed tumor growth in nude mice in a dose-dependent manner. [4]

Clinical trial: A phase I study was 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 was noticed that this kind of compounds could be well tolerated and has sufficient activity. 1,200 mg once daily was a recommended dose for further study. [5]

参考文献:
[1] LaGreca S, Arcari J, Baker D, Borzillo G, Chen J, Clark T, Cohen B, Hungerford W, Kakar S, Kanter A, Knauth K, Lu Y, Martinez-Alsina L, Marx M, Patel N, Soderstrom C, Tkalcevic G, Thompson C, Troutman M, Vincent P, Wessel M.? Identification of selective, orally active Tie2 kinase inhibitors and discovery of CE-245,677 and PF-371,989. Cancer Res. 2007 May; 67: 3259.
[2] Liu L , Lina T, Coleb A, Wenc R, Zhao L, Bresciab MR, Jacoba B, Hussainb Z, Appella K, Hendersonb I, Webba M.? dentification and characterization of small-molecule inhibitors of Tie2 kinase. FEBS Lett. 2008 Mar; 582(5): 785-91.
[3] Semones M, Feng Y, Johnson N, Adams JL, Winkler J, Hansbury M.? Pyridinylimidazole inhibitors of Tie2 kinase. Bioorg Med Chem Lett. 2007 Sep; 17(17): 4756-60.
[4]Hasenstein JR, Kasmerchak K, Buehler D, Hafez GR, Claery K, Moody JS, Kozak KR.? Efficacy of Tie2 receptor antagonism in angiosarcoma. Neoplasia 2012 Feb;14(2):131-40.
[5] Garcia-Manero G, Khoury HJ, Jabbour E, Lancet J, Winski SL, Cable L, Rush S, Maloney L, Hogeland G, Ptaszynski M, Calvo MC, Bohannan Z, Kantarjian H, Komrokji R.? A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clin Cancer Res. 2015 Mar 1;21(5):985-94.