Tie2 kinase inhibitor

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]

References:
[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.

The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2.[Pubmed:12609966]

Circ Res. 2003 Apr 4;92(6):630-6.

Tie2 is a receptor tyrosine kinase expressed predominantly in endothelial cells and is essential for blood vessel formation and maintenance. The receptor has potent antiinflammatory effects on endothelial cells, suppressing vascular endothelial growth factor- and tumor necrosis factor-induced expression of leukocyte adhesion molecules and procoagulant tissue factor and inhibiting vascular leakage. To delineate the signaling pathways utilized by Tie2, we performed yeast two-hybrid screening of a human endothelial cell cDNA library and identified a novel protein interacting with the intracellular domain of the receptor. This protein was found to be human A20 binding inhibitor of NF-kappaB activation-2, ABIN-2, an inhibitor of NF-kappaB-mediated inflammatory gene expression. Coexpression of Tie2 and ABIN-2 in CHO cells confirmed the interaction occurs in mammalian cells. In contrast, Tie1 did not interact with ABIN-2 in the yeast two-hybrid system or mammalian cells. Deletion analysis identified the Tie2 binding motif to be encompassed between residues 171 and 272 in ABIN-2. Interaction was dependent on Tie2 autophosphorylation but ABIN-2 was not tyrosine phosphorylated by Tie2. Furthermore, in endothelial cells the interaction was stimulated by the Tie2 ligand angiopoietin-1. Expression of ABIN-2 deletion mutants in endothelial cells suppressed the ability of angiopoietin-1 to inhibit phorbol ester-stimulated NF-kappaB-dependent reporter gene activity. These findings provide the first direct link between Tie2 and a key regulator of inflammatory responses in endothelial cells. Interaction between Tie2 and ABIN-2 may be important in the vascular protective antiinflammatory actions of Tie2.

The first naturally occurring Tie2 kinase inhibitor.[Pubmed:11735581]

Org Lett. 2001 Dec 13;3(25):4047-9.

[structure: see text] Bioassay-guided fractionation of the plant Acacia aulacocarpa, guided by a bioassay for Tie2 tyrosine kinase activity, yielded the novel triterpene 3,21-dioxo-olean-18-en-oic acid (1) as the first naturally occurring non-protein inhibitor of Tie2 kinase. The structure of 1 was assigned by analysis of spectral data. In addition to its activity as an inhibitor of Tie2 kinase, compound 1 also shows modest activity against a variety of cultured mammalian cells.

Tie2 kinase inhibitor 1 (compound 5) is a potent, selective Tie2 kinase inhibitor with an IC50 of 250 nM. Tie2 kinase inhibitor 1 has anti-cancer activity.

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