Target Validation Information
Target ID T81892
Target Name mRNA of Inhibitor of apoptosis protein
Target Type
Clinical Trial
Drug Potency against Target SM-337 Drug Info Ki = 110.9 nM [531078]
EMBELIN Drug Info IC50 = 4100 nM [527061]
ARPFAQK-FAM Drug Info IC50 = 570 nM [527061]
SM-131 Drug Info Ki = 61 nM [529809]
AVPIAQKSEK-FAM Drug Info IC50 = 2800 nM [527061]
SM-122 Drug Info IC50 = 635.7 nM [531078]
Action against Disease Model AEG35156 AEG35156 (a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis) reduced XIAP mRNA levels with an EC50 of 8 to 32 nmol/L and decreased XIAP protein levels by >80%. Loss of XIAP protein correlated with increased sensitization to t uMor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in Panc-1 pancreatic carcinoma cells. AEG35156 exhibited potent antit uMor activity relative to control oligonucleotides in three h uMan cancer xenograft models (prostate, colon, and lung) and was capable of inducing complete t uMor regression when combined with taxanes. Antit uMor effects of AEG35156 correlated with suppression of t uMor XIAP levels. [552635] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Mutations in the X-linked inhibitor of apoptosis (XIAP) have recently been identified in patients with the rare genetic disease, X-linked lymphoproliferative syndrome (XLP), which was previously thought to be solely attributable to mutations in a distinct gene, SAP. To further understand the roles of these two factors in the pathogenesis of XLP, we have compared mice deficient in Xiap with known phenotypes of Sap-null mice. We show here that in contrast to Sap-deficient mice, animals lacking Xiap have apparently normal NKT cell development and no apparent defect in h uMoral responses to T cell-dependent antigens. However, Xiap-deficient cells were more susceptible to death upon infection with the murine herpesvirus MHV-68 and gave rise to more infectious virus. Thesedifferences could be rescued by restoration of XIAP. These data provide insight into the differing roles of XIAP and SAP in the pathogenesis of XLP [531078]
References
Ref 531078J Med Chem. 2010 Sep 9;53(17):6361-7.Nonpeptidic and potent small-molecule inhibitors of cIAP-1/2 and XIAP proteins.
Ref 552635Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis. Clin Cancer Res. 2006 Sep 1;12(17):5231-41.
Ref 527061J Med Chem. 2004 May 6;47(10):2430-40.Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database.
Ref 527061J Med Chem. 2004 May 6;47(10):2430-40.Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database.
Ref 529809J Med Chem. 2008 Dec 11;51(23):7352-5.Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases.
Ref 527061J Med Chem. 2004 May 6;47(10):2430-40.Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database.
Ref 531078J Med Chem. 2010 Sep 9;53(17):6361-7.Nonpeptidic and potent small-molecule inhibitors of cIAP-1/2 and XIAP proteins.

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