| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T02677 | ||||
| Target Name | Baculoviral IAP repeat-containing protein 5 | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | Terameprocol | Drug Info | IC50 = 200 nM | [552775] | |
| Action against Disease Model | Terameprocol | Potent anticancer activity in t uMour cell lines and animal models; good safety and efficacy profile in patients with head and neck or squamous cell carcinoma (intrat uMoral administration) and in patients with cervical dysplasia (intravaginal administration). | [537564] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | We show that cardiac-specific deletion of survivin resulted in premature cardiac death. The underlying cause was a dramatic reduction in total cardiomyocyte n uMbers as determined by a stereological method for quantification of cells per organ. The resulting increased hemodynamic load per cell led to progressive heart failure as assessed by echocardiography, magnetic resonance imaging, positron emission tomography, and invasive catheterization. The reduction in total cardiomyocyte n uMber in alpha-myosin heavy chain (MHC)-survivin(-/-) mice was due to an approximately 50% lower mitotic rate without increased apoptosis. This occurred at the expense of DNA acc uMulation because survivin-deficient cardiomyocytes displayed marked DNA polyploidy indicative of consecutive rounds of DNA replication without cell division. Survivin small interfering RNA knockdown in neonatal rat cardiomyocytes also led to polyploidization and cell cycle arrest without apoptosis. Adenoviral overexpression of survivin in cardiomyocytes inhibited doxorubicin-induced apoptosis, induced DNA synthesis, and promoted cell cycle progression. The phenotype of the alphaMHC-survivin(-/-) mice also allowed us to determine the minim uM cardiomyocyte n uMber sufficient for normal cardiac function. In h uMan cardiomyopathy, survivin was potently induced in the failing heart and downregulated again after hemodynamic support by a left ventricular assist device. Its expression positively correlated with the mean cardiomyocyte DNA content. | [537564] | |||
| References | |||||
| Ref 537564 | Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66. | ||||
| Ref 552775 | Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells. Br J Cancer. 2008 Jan 29;98(2):345-55. doi: 10.1038/sj.bjc.6604160. Epub 2008 Jan 15. | ||||
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