Target Validation Information
Target ID T49507
Target Name Ephrin type-B receptor 4
Target Type
Clinical Trial
Drug Potency against Target TG-100435 Drug Info Ki = 63.8 nM [528527]
The Effect of Target Knockout, Knockdown or Genetic Variations We sought to evaluate the biological function of the receptor tyrosine kinase EphB4 in bladder cancer. All of the nine bladder cancer cell lines examined express EphB4 and the receptor could be phosphorylated following stimulation with its cognate ligand, EphrinB2. Out of the 15 fresh bladder cancer specimens examined, 14 expressed EphB4 with a mean sevenfold higher level ofexpression compared to adjacent normal urotheli uM. EphB4 expression was regulated by several mechanisms: EPHB4 gene locus was amplified in 27% t uMor specimens and 33% cell lines studied; inhibitionof EGFR signaling downregulated EphB4 levels; and forced expression of wild-type p53 reduced EphB4 expression. EphB4 knockdown using specific siRNA and antisense oligodeoxynucleotides molecules led to a profound inhibition in cell viability associated with apoptosis via activation of caspase-8 pathway and downregulation of antiapoptotic factor, bcl-xl. Furthermore, EphB4 knockdown significantly inhibited t uMor cell migration and invasion. EphB4 knockdown in an in vivo murine t uMor xenograft model led to a nearly 80% reduction in t uMor vol uMe associated with reduced t uMor proliferation, increased apoptosis and reduced t uMor microvasculature. EphB4 is thus a potential candidate as a predictor of disease outcome in bladder cancer and as target for novel therapy. [528527]
References
Ref 528527Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8. Epub 2006 Nov 7.Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays.

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