| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T86385 | ||||
| Target Name | Cathepsin G | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | Delanzomib | Drug Info | IC50 = 2110 nM | [529283] | |
| Aloxistatin | Drug Info | IC50 = 1100 nM | [528870] | ||
| JNJ-10311795 | Drug Info | Ki = 38 nM | [528733] | ||
| Action against Disease Model | Dermolastin | N-glycosylation and biological activity of recombinant h uMan alpha1-antitrypsin expressed in a novel h uMan neuronal cell line. | [553098] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Bilateral renal ischemia led to the expiration of 64% of wild-type mice within 4 days of reperfusion, whereas all cathepsin G-deficient mice survived. Ser uM creatinine increased to similar levels at 24 hours after reperfusion and then decreased to background in both groups of mice. Ischemic kidneys from both groups had similar levels of neutrophil infiltration and of CXCL1,CXCL2, and myeloperoxidase protein 9 hours after reperfusion, but at 24 hours, these acute inflammatory response components were decreased more than 50% in kidneys from cathepsin G-deficient versus wild-type mice. Ischemic kidneys from surviving wild-type mice had severe tubular necrosis and tubular cell apoptosis 24 hours after reperfusion with subsequent development of fibrosis 30 days later. In contrast, ischemic kidneys from cathepsin G-deficient mice had a 70% decrease in tubular cell apoptosis with little detectable collagen deposition. These data identify cathepsin G as a critical component sustaining neutrophil-mediated acute tissue pathology and subsequent fibrosis after renal ischemia/reperfusion injury | [529283] | |||
| References | |||||
| Ref 529283 | J Med Chem. 2008 Feb 28;51(4):1068-72. Epub 2008 Feb 5.Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. | ||||
| Ref 528870 | J Biol Chem. 2007 Jul 20;282(29):20836-46. Epub 2007 May 29.Inhibition of the activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing. | ||||
| Ref 553098 | N-glycosylation and biological activity of recombinant human alpha1-antitrypsin expressed in a novel human neuronal cell line. Biotechnol Bioeng. 2011 Sep;108(9):2118-28. doi: 10.1002/bit.23158. Epub 2011 Apr 20. | ||||
| Ref 528733 | J Med Chem. 2007 Apr 19;50(8):1727-30. Epub 2007 Mar 16.Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase. | ||||
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