Target Validation Information
Target ID T68290
Target Name Cathepsin S
Target Type
Clinical Trial
Drug Potency against Target P2,P3 Ketoamide derivative Drug Info IC50 = 130 nM [1]
Cbz-Ile-Phe-Ala-LeuVSMe Drug Info IC50 = 9000 nM [2]
Ac-hPhe-Leu-Gly-LeuVSMe Drug Info IC50 = 12000 nM [2]
N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile Drug Info Ki = 4100 nM [3]
N-(tert-butoxycarbonyl)-norvalyl-glycine-nitrile Drug Info Ki = 900 nM [3]
N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile Drug Info Ki = 550 nM [3]
N-(tert-butoxycarbonyl)-valyl-glycine-nitrile Drug Info Ki = 6200 nM [3]
Cbz-Ile-MetO2-Ala-LeuVSMe Drug Info IC50 = 13000 nM [2]
Ac-hPhe-Leu-Phe-LeuVSMe Drug Info IC50 = 150 nM [2]
BOCEPREVIR Drug Info IC50 = 120 nM [4]
6-(3-(trifluoromethyl)phenyl)picolinonitrile Drug Info IC50 = 2884 nM [5]
L-006235-1 Drug Info IC50 = 318 nM [6]
4-cycloheptyl-6-propylpyrimidine-2-carbonitrile Drug Info IC50 = 1300 nM [7]
4-propyl-6-m-tolylpyrimidine-2-carbonitrile Drug Info IC50 = 950 nM [8]
Cbz-Ile-hPhe-Ala-LeuVSMe Drug Info IC50 = 10000 nM [2]
Cbz-Glu(OtBu)-Ala-LeuVSMe Drug Info IC50 = 3000 nM [2]
Cbz-Ile-t-ButylGln-Ala-LeuVSMe Drug Info IC50 = 3300 nM [2]
Cbz-Ile-Leu-Ala-LeuVSMe Drug Info IC50 = 700 nM [2]
Cbz-Ile-t-ButylhomoGlu-Ala-LeuVSMe Drug Info IC50 = 7100 nM [2]
Ac-hPhe-Leu-Ala-LeuVSMe Drug Info IC50 = 6900 nM [2]
Cbz-Ile-Pro-Ala-LeuVSMe Drug Info IC50 = 13000 nM [2]
N-(benzyloxycarbonyl)-leucyl-glycine-nitrile Drug Info Ki = 130 nM [3]
N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile Drug Info Ki = 130 nM [3]
4-cyclooctyl-6-propylpyrimidine-2-carbonitrile Drug Info IC50 = 2239 nM [7]
N-(2-naphthylsulfonyl)-glycyl-glycine-nitrile Drug Info Ki = 2500 nM [3]
N-(tert-butoxycarbonyl)-tyrosyl-glycine-nitrile Drug Info Ki = 970 nM [3]
L-873724 Drug Info IC50 = 2441 nM [9]
CRA-028129 Drug Info IC50 = 30~100 nM
N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile Drug Info Ki = 660 nM [3]
N-benzoyl-phenylalanyl-glycine-nitrile Drug Info Ki = 77 nM [3]
N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile Drug Info Ki = 240 nM [3]
GNF-PF-5434 Drug Info Ki < 0.1 nM [10]
N-acetyl-phenylalanyl-glycine-nitrile Drug Info Ki = 1400 nM [3]
N-(1-oxobutan-2-yl)-3-(trifluoromethyl)benzamide Drug Info IC50 = 1070 nM [11]
Action against Disease Model CRA-028129 CRA-028129, a pico molar Cat S inhibitor, has nano molar activity in a cellular assay [12] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations H uMan atherosclerotic lesions overexpress the lysosomal cysteine protease cathepsin S (Cat S), one of the most potent mammalian elastases known. In contrast, atheromata have low levels of the endogenous Cat S inhibitor cystatin C compared with normal arteries, suggesting involvement of this protease in atherogenesis. The present study tested this hypothesis directly by crossing Cat S-deficient (CatS(-/-)) mice with LDL receptor-deficient (LDLR(-/-)) mice that develop atherosclerosis on a high-cholesterol diet. Compared with LDLR(-/-) mice, double-knockout mice (CatS(-/-)LDLR(-/-)) developed significantly less atherosclerosis, as indicated by plaque size (plaque area and intimal thickening) and stage of development. These mice also had markedly reduced content of intimal macrophages, lipids, smooth muscle cells, collagen, CD4(+) T lymphocytes, and levels of IFN-gamma. CatS(-/-)LDLR(-/-) monocytes showed impaired subendothelial basement membrane transmigration, and aortas from CatS(-/-)LDLR(-/-) mice had preserved elastic laminae. These findings establish a pivotal role for Cat S in atherogenesis [1]
References
REF 1Bioorg Med Chem Lett. 2004 Oct 4;14(19):4897-902.Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions.
REF 2J Med Chem. 2006 May 18;49(10):2953-68.Optimization of subsite binding to the beta5 subunit of the human 20S proteasome using vinyl sulfones and 2-keto-1,3,4-oxadiazoles: syntheses and cellular properties of potent, selective proteasome inhibitors.
REF 3J Med Chem. 2005 Dec 1;48(24):7688-707.Interaction of papain-like cysteine proteases with dipeptide-derived nitriles.
REF 4Antimicrob Agents Chemother. 2010 Jan;54(1):305-11. Epub 2009 Oct 19.MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.
REF 5Bioorg Med Chem Lett. 2010 Aug 1;20(15):4507-10. Epub 2010 Jun 10.4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.
REF 6J Med Chem. 2005 Dec 1;48(24):7535-43.Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity.
REF 7Bioorg Med Chem Lett. 2010 Mar 1;20(5):1524-7. Epub 2010 Jan 25.Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors.
REF 8Bioorg Med Chem Lett. 2010 Aug 1;20(15):4447-50. Epub 2010 Jun 15.2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors.
REF 9Bioorg Med Chem Lett. 2007 Sep 1;17(17):4929-33. Epub 2007 Jun 10.The identification of potent, selective, and bioavailable cathepsin S inhibitors.
REF 10Bioorg Med Chem. 2009 Feb 1;17(3):1064-70. Epub 2008 Feb 7.Substrate optimization for monitoring cathepsin C activity in live cells.
REF 11Bioorg Med Chem Lett. 2010 Dec 1;20(23):6890-4. Epub 2010 Oct 26.Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.
REF 12Prostaglandin receptor signaling in disease. ScientificWorldJournal. 2007 Sep 1;7:1329-47.

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