Target Information

Target General Infomation
Target ID
T68290
Former ID
TTDC00067
Target Name
Cathepsin S
Gene Name
CTSS
Synonyms
Cysteine protease cathepsin S; CTSS
Target Type
Clinical Trial
Disease Autoimmune diabetes [ICD10: E08-E13]
Asthma [ICD10: J45]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Cardiovascular disorder [ICD10: I00-I99]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Neuropathic pain [ICD9: 356.0, 356.8; ICD10: G64, G90.0]
Psoriatic disorder [ICD9: 696; ICD10: L40]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Function
Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules. The bond- specificity of this proteinase is in part similar to the specificities of cathepsin L and cathepsin N.
BioChemical Class
Peptidase
Target Validation
T68290
UniProt ID
P25774
EC Number
EC 3.4.22.27
Sequence
MKRLVCVLLVCSSAVAQLHKDPTLDHHWHLWKKTYGKQYKEKNEEAVRRLIWEKNLKFVM
LHNLEHSMGMHSYDLGMNHLGDMTSEEVMSLMSSLRVPSQWQRNITYKSNPNRILPDSVD
WREKGCVTEVKYQGSCGACWAFSAVGALEAQLKLKTGKLVSLSAQNLVDCSTEKYGNKGC
NGGFMTTAFQYIIDNKGIDSDASYPYKAMDQKCQYDSKYRAATCSKYTELPYGREDVLKE
AVANKGPVSVGVDARHPSFFLYRSGVYYEPSCTQNVNHGVLVVGYGDLNGKEYWLVKNSW
GHNFGEEGYIRMARNKGNHCGIASFPSYPEI
Drugs and Mode of Action
Drug(s) SAR-114137 Drug Info Phase 1 Pain [1]
VBY- 036 Drug Info Phase 1 Neuropathic pain [2]
VBY- 891 Drug Info Phase 1 Autoimmune diabetes [3]
VBY-129 Drug Info Phase 1 Autoimmune diabetes [4]
RG-7236 Drug Info Discontinued in Phase 1 Cardiovascular disorder [5]
CRA-028129 Drug Info Terminated Psoriatic disorder [6]
Inhibitor 2-[(2',3',4'-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL Drug Info [7]
4-cycloheptyl-6-propylpyrimidine-2-carbonitrile Drug Info [8]
4-cyclooctyl-6-propylpyrimidine-2-carbonitrile Drug Info [8]
4-propyl-6-m-tolylpyrimidine-2-carbonitrile Drug Info [9]
6-(3-(trifluoromethyl)phenyl)picolinonitrile Drug Info [10]
Ac-hPhe-Leu-Ala-LeuVSMe Drug Info [11]
Ac-hPhe-Leu-Gly-LeuVSMe Drug Info [11]
Ac-hPhe-Leu-Phe-LeuVSMe Drug Info [11]
AM-3840 Drug Info [12]
BF/PC-18 Drug Info [12]
Cbz-Glu(OtBu)-Ala-LeuVSMe Drug Info [11]
Cbz-Ile-hPhe-Ala-LeuVSMe Drug Info [11]
Cbz-Ile-Leu-Ala-LeuVSMe Drug Info [11]
Cbz-Ile-MetO2-Ala-LeuVSMe Drug Info [11]
Cbz-Ile-Phe-Ala-LeuVSMe Drug Info [11]
Cbz-Ile-Pro-Ala-LeuVSMe Drug Info [11]
Cbz-Ile-t-ButylGln-Ala-LeuVSMe Drug Info [11]
Cbz-Ile-t-ButylhomoGlu-Ala-LeuVSMe Drug Info [11]
Clik60 Drug Info [13]
compound (R)-26 Drug Info [14]
CRA-028129 Drug Info [15]
E-64 Drug Info [16]
Fucose Drug Info [17]
GNF-PF-5434 Drug Info [18]
JNJ-10329670 Drug Info [12]
L-006235-1 Drug Info [19]
L-873724 Drug Info [20]
N-(1-oxobutan-2-yl)-3-(trifluoromethyl)benzamide Drug Info [21]
N-(2-naphthylsulfonyl)-glycyl-glycine-nitrile Drug Info [22]
N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile Drug Info [22]
N-(benzyloxycarbonyl)-leucyl-glycine-nitrile Drug Info [22]
N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile Drug Info [22]
N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile Drug Info [22]
N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile Drug Info [22]
N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile Drug Info [22]
N-(tert-butoxycarbonyl)-norvalyl-glycine-nitrile Drug Info [22]
N-(tert-butoxycarbonyl)-tyrosyl-glycine-nitrile Drug Info [22]
N-(tert-butoxycarbonyl)-valyl-glycine-nitrile Drug Info [22]
N-acetyl-phenylalanyl-glycine-nitrile Drug Info [22]
N-benzoyl-phenylalanyl-glycine-nitrile Drug Info [22]
P2,P3 Ketoamide derivative Drug Info [23]
RG-7236 Drug Info [12]
SAR-114137 Drug Info [1]
VBY- 036 Drug Info [24]
VBY- 285 Drug Info [12]
VBY-129 Drug Info [25]
Modulator VBY- 891 Drug Info [12]
Pathways
KEGG Pathway Lysosome
Phagosome
Antigen processing and presentation
Tuberculosis
NetPath Pathway Leptin Signaling Pathway
IL2 Signaling Pathway
Reactome Endosomal/Vacuolar pathway
Degradation of the extracellular matrix
Trafficking and processing of endosomal TLR
Assembly of collagen fibrils and other multimeric structures
MHC class II antigen presentation
WikiPathways Class I MHC mediated antigen processing &amp
presentation
Trafficking and processing of endosomal TLR
References
REF 1From laboratory to pilot plant: the solid-state process development of a highly potent cathepsin S/K inhibitor. Eur J Pharm Biopharm. 2013 Apr;83(3):436-48.
REF 2ClinicalTrials.gov (NCT01892891) Safety Study of VBY-036 in Healthy Volunteers After 7 Days of Oral Dosing. U.S. National Institutes of Health.
REF 3ClinicalTrials.gov (NCT01947738) Safety Study of VBY-891 in Healthy Volunteers After Single or Multiple (7 Days) of Oral Dosing (VBY891P1). U.S. National Institutes of Health.
REF 4Clinical pipeline report, company report or official report of ViroBay.
REF 5Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033628)
REF 6Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022029)
REF 7The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 8Bioorg 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 9Bioorg 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 10Bioorg 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 11J 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 12(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2353).
REF 13Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J Clin Invest. 2002 Aug;110(3):361-9.
REF 14Selective nitrile inhibitors to modulate the proteolytic synergism of cathepsins S and F. J Med Chem. 2012 Jun 28;55(12):5982-6.
REF 15Phase I clinical trial for cathepsin S inhibitor for psoriasis begins. Celera Genomics. 2005.
REF 16Baculoviral expression and characterization of rodent cathepsin S. Protein Expr Purif. 2001 Oct;23(1):45-54.
REF 17How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 18Bioorg Med Chem. 2009 Feb 1;17(3):1064-70. Epub 2008 Feb 7.Substrate optimization for monitoring cathepsin C activity in live cells.
REF 19J 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 20Bioorg 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 21Bioorg Med Chem Lett. 2010 Dec 1;20(23):6890-4. Epub 2010 Oct 26.Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.
REF 22J Med Chem. 2005 Dec 1;48(24):7688-707.Interaction of papain-like cysteine proteases with dipeptide-derived nitriles.
REF 23Bioorg 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 24Clinical pipeline report, company report or official report of ViroBay.
REF 25Clinical pipeline report, company report or official report of ViroBay.

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