Target Validation Information
Target ID T92144
Target Name Angiopoietin 1 receptor
Target Type
Clinical Trial
Drug Potency against Target CEP-11981 Drug Info EC50 = 10.9 nM [552643]
(4-Phenoxy-phenyl)-quinazolin-4-yl-amine Drug Info IC50 = 17870 nM [525876]
A-420983 Drug Info IC50 = 1484 nM [527057]
Action against Disease Model CEP-11981 CEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy)-fused pyrrolocarbazole with potent pan-vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity. Reductions in neurologic dysfunction, brain edema, hemorrhage, and intrat uMoral microvessel density (CD34 staining) were observed in glioma-bearing mice receiving CEP-7055 alone, temozolomide alone, and the combination of CEP-7055 and temozolomide relative to vehicle and to temozolomide monotherapy. The administration of CEP-7055 in combination withirinotecan (20 mg/kg/dose i.p. ???5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed reductions on primary colon carcinoma and hepatic metastatic burden in the CT-26 t uMormodel relative to that achieved by irinotecan and oxaliplatin monotherapy. [551594] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the n uMber and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability tomodulate the vascular response after injury [551594]
References
Ref 551594The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice. Mol Cancer Ther. 2006 Jul;5(7):1744-53.
Ref 552643Therapeutic potential of monoamine transporter substrates. Curr Top Med Chem. 2006;6(17):1845-59.
Ref 525876Bioorg Med Chem Lett. 2000 Oct 2;10(19):2167-70.Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I.
Ref 527057Bioorg Med Chem Lett. 2004 May 17;14(10):2613-6.A-420983: a potent, orally active inhibitor of lck with efficacy in a model of transplant rejection.

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