| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T29879 | ||||
| Target Name | Integrin alpha-5 | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | JSM 6427 | Drug Info | IC50 = 0.55 nM | [552709] | |
| C(-GRGDfL-) | Drug Info | IC50 = 740 nM | [529125] | ||
| Action against Disease Model | JSM 6427 | JSM6427 provided a dose-dependent blockade of ARPE-19 cell adhesion to fibronectin (IC(50), 7.1 +/- 2.5 microM) and inhibition of migration (IC(50), 6.0 +/- 4.5 microM). In the rabbit model, intravitreal injection of JSM6427 provided significant inhibition of proliferation of retinal cells (M?1ller cells, microglia, and macrophages) on days 3 and 7 after detachment and inhibition of inflammatory response and retinal scarring on day 7 after detachmen | [552988] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Integrin cell adhesion receptors and fibronectin, one of their extracellular matrix ligands, have been demonstrated to be important for angiogenesis using functional perturbation studies and complete knockout mouse models. Here, we report on the roles of the alpha5 and alphav integrins, which are the major endothelial fibronectin receptors, in developmental angiogenesis. We generated an integrin alpha5-floxed mouse line and ablated alpha5 integrin in endothelial cells. Unexpectedly, endothelial-specific knockout of integrin alpha5 has no obvious effect on developmental angiogenesis. We provide evidence for genetic interaction between mutations in integrin alpha5 and alphav and for overlapping functions and compensation between these integrins and perhaps others. Nonetheless, in embryos lacking both alpha5 and alphav integrins in their endothelial cells, initial vasculogenesis and angiogenesis proceed normally, at least up to E11.5, including the formation of apparently normal embryonic vasculature and development of the branchial arches. However, in the absence of endothelial alpha5 and alphav integrins, but not of either alone, there are extensive defects inremodeling of the great vessels and heart resulting in death at ~E14.5. We also found that fibronectin assembly is somewhat affected in integrin alpha5 knockout endothelial cells and markedly reducedin integrin alpha5/alphav double-knockout endothelial cell lines. Therefore, neither alpha5 nor alphav integrins are required in endothelial cells for initial vasculogenesis and angiogenesis, although they are required for remodeling of the heart and great vessels. These integrins on other cells, and/or other integrins on endothelial cells, might contribute to fibronectin assembly and vascular development. | [552709] | |||
| References | |||||
| Ref 552709 | Inhibition of inflammatory lymphangiogenesis by integrin alpha5 blockade. Am J Pathol. 2007 Jul;171(1):361-72. | ||||
| Ref 529125 | J Med Chem. 2007 Nov 29;50(24):5878-81. Epub 2007 Nov 1.Multiple N-methylation by a designed approach enhances receptor selectivity. | ||||
| Ref 552988 | Assessment of the integrin alpha5beta1 antagonist JSM6427 in proliferative vitreoretinopathy using in vitro assays and a rabbit model of retinal detachment. Invest Ophthalmol Vis Sci. 2010 Feb;51(2):1028-35. doi: 10.1167/iovs.09-3575. Epub 2009 Oct 8. | ||||
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