Pyridinylimidazole inhibitors of Tie2 kinase

Semones, Marcus A.; Feng, Yuping; Johnson, Neil W.; Adams, Jerry L.; Winkler, Jim; Hansbury, Michael

doi:10.1016/j.bmcl.2007.06.068

Cited by 33 publications

(27 citation statements)

References 9 publications

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“…The TIE2-TKI compound has been designed to potently inhibit the TIE2-WT kinase (33). Our results indicate that it has a reduced ability to target the L914F mutant TIE2.…”

Section: Discussionmentioning

confidence: 90%

“…injection from day 1 to day 14 (schematic in Figure 3A). We reached the maximum solubility of TIE2-TKI compound in vehicle at 10 mg/ kg, a dose effective for reducing tumor growth of MOPC-315 xenografts (33). The rapamycin injected dose was 2 mg/kg, which was found effective in preventing blood vessel formation in a murine model of infantile hemangioma (34) and in preventing tumor growth and vascular permeability in a model of glioma (35).…”

Section: Tie2 Mutation L914f Is Sufficient To Induce Huvecs To Form Vmentioning

confidence: 92%

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Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects

Boscolo¹,

Limaye²,

Huang³

et al. 2015

Journal of Clinical Investigation

189

235

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R e s e a R c h a R t i c l e3 4 9 2 jci.org Volume 125 Number 9 September 2015Other factors are likely involved, since over 80 genes were differentially expressed (at least 2-fold) in the TIE2-L914F endothelial cells compared with WT (30). We hypothesized that mutant TIE2 in endothelial cells is sufficient to cause VM. Here, we show that HUVECs engineered to Previous studies on mutant TIE2 showed that expression of TIE2-L914F or TIE2-R849W in HUVECs increased activation of AKT and of . Elevated AKT signaling in these cells has been linked to increased survival (29, 30) and to reduced production of PDGF-B (30), a major player in mural cell recruitment.

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“…The TIE2-TKI compound has been designed to potently inhibit the TIE2-WT kinase (33). Our results indicate that it has a reduced ability to target the L914F mutant TIE2.…”

Section: Discussionmentioning

confidence: 90%

Section: Tie2 Mutation L914f Is Sufficient To Induce Huvecs To Form Vmentioning

confidence: 92%

Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects

Boscolo¹,

Limaye²,

Huang³

et al. 2015

Journal of Clinical Investigation

189

235

View full text Add to dashboard Cite

show abstract

“…PI3 K activates Akt which in turn phosphorylates and activates the Forkhead transcription factor FOXO-1 (FKHR-1). FKHR-1 is a strong inducer of Ang-2 expression and inhibits Ang-2 liberation [71][72][73][74][75]. Activation of Akt also stimulates the phosphorylation and thereby the inhibition of pro-apoptotic proteins, including BAD and procaspase-9 [72,76].…”

Section: Endothelial Cell Survival and Maintenancementioning

confidence: 99%

The role of the Angiopoietins in vascular morphogenesis

2009

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The Angiopoietin/Tie system acts as a vascular specific ligand/receptor system to control endothelial cell survival and vascular maturation. The Angiopoietin family includes four ligands (Angiopoietin-1, Angiopoietin-2 and Angiopoietin-3/4) and two corresponding tyrosine kinase receptors (Tie1 and Tie2). Ang-1 and Ang-2 are specific ligands of Tie2 binding the receptor with similar affinity. Tie2 activation promotes vessel assembly and maturation by mediating survival signals for endothelial cells and regulating the recruitment of mural cells. Ang-1 acts in a paracrine agonistic manner inducing Tie2 phosphorylation and subsequent vessel stabilization. In contrast, Ang-2 is produced by endothelial cells and acts as an autocrine antagonist of Ang-1-mediated Tie2 activation. Ang-2 thereby primes the vascular endothelium to exogenous cytokines and induces vascular destabilization at higher concentrations. Ang-2 is strongly expressed in the vasculature of many tumors and it has been suggested that Ang-2 may act synergistically with other cytokines such as vascular endothelial growth factor to promote tumor-associated angiogenesis and tumor progression. The better mechanistic understanding of the Ang/Tie system is gradually paving the way toward the rationale exploitation of this vascular signaling system as a therapeutic target for neoplastic and non-neoplastic diseases.

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“…A total of 263 compounds were obtained [13][14][15][16][17][18][19][20][21]. From these compounds a quantitative pharmacophore model was developed with the aid of HypoRefine module within Catalyst [22].…”

Section: Introductionmentioning

confidence: 99%