Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUMQVO)

• DTT Name: Cathepsin S (CTSS)
• Synonyms: Cysteine protease cathepsin S
• Gene Name: CTSS
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: CATS_HUMAN
• TTD ID: T68290
• EC Number: EC 3.4.22.27
• Sequence:
  MKRLVCVLLVCSSAVAQLHKDPTLDHHWHLWKKTYGKQYKEKNEEAVRRLIWEKNLKFVM
  LHNLEHSMGMHSYDLGMNHLGDMTSEEVMSLMSSLRVPSQWQRNITYKSNPNRILPDSVD
  WREKGCVTEVKYQGSCGACWAFSAVGALEAQLKLKTGKLVSLSAQNLVDCSTEKYGNKGC
  NGGFMTTAFQYIIDNKGIDSDASYPYKAMDQKCQYDSKYRAATCSKYTELPYGREDVLKE
  AVANKGPVSVGVDARHPSFFLYRSGVYYEPSCTQNVNHGVLVVGYGDLNGKEYWLVKNSW
  GHNFGEEGYIRMARNKGNHCGIASFPSYPEI
• Function: 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. Thiol protease.
• KEGG Pathway:
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Antigen processing and presentation (hsa04612)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  MHC class II antigen presentation (R-HSA-2132295)
  Endosomal/Vacuolar pathway (R-HSA-1236977)

Molecular Interaction Atlas (MIA) of This DTT

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RG7625	DMDGPKS	Autoimmune disease	4A40-4A45	Phase 2	[1]
SAR-114137	DMZ1XR5	Pain	MG30-MG3Z	Phase 1	[2]
VBY- 036	DMULRYC	Neuropathic pain	8E43.0	Phase 1	[3]
VBY- 891	DMTKPH4	Autoimmune diabetes	5A10	Phase 1	[4]
VBY-129	DM4YIWK	Autoimmune diabetes	5A10	Phase 1	[5]

10 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Oxotetrahydro-2-H-furo[3.2-b]pyrrol-4(5-H)-yl derivative 1	DM1SH5R	Pain	MG30-MG3Z	Patented	[6]
Phenylalanine derivative 1	DMVYP8K	Glioma	2A00.0	Patented	[6]
PMID25399719-Compound-17	DMRXKJZ	N. A.	N. A.	Patented	[7]
PMID27998201-Compound-12	DM8QZNC	Bone cancer	2B5Z	Patented	[6]
PMID27998201-Compound-15	DMOB8LU	Pain	MG30-MG3Z	Patented	[6]
PMID27998201-Compound-17	DMAZVHJ	Hair loss	ED70	Patented	[6]
PMID27998201-Compound-5	DMVZ0ND	Chronic obstructive pulmonary disease	CA22	Patented	[6]
PMID27998201-Compound-6	DM0LGTY	N. A.	N. A.	Patented	[6]
PMID27998201-Compound-7	DMU4QYR	Abdominal aortic aneurysm	BD50.4	Patented	[6]
PMID27998201-Compound-9	DM1JOZN	Rheumatoid arthritis	FA20	Patented	[6]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RG-7236	DMDPWCM	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 1	[4]
CRA-028129	DMRNB7V	Psoriatic disorder	EA90	Terminated	[10]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-006235-1	DMMEH12	Osteoarthritis	FA00-FA05	Preclinical	[8]
RO5461111	DMRT3FK	Systemic lupus erythematosus	4A40.0	Preclinical	[9]

41 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-[(2',3',4'-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL	DMR4LJY	Discovery agent	N.A.	Investigative	[11]
4-cycloheptyl-6-propylpyrimidine-2-carbonitrile	DMNT5BF	Discovery agent	N.A.	Investigative	[12]
4-cyclooctyl-6-propylpyrimidine-2-carbonitrile	DMS42TN	Discovery agent	N.A.	Investigative	[12]
4-propyl-6-m-tolylpyrimidine-2-carbonitrile	DMNM4GE	Discovery agent	N.A.	Investigative	[13]
6-(3-(trifluoromethyl)phenyl)picolinonitrile	DMDYQE2	Discovery agent	N.A.	Investigative	[14]
Ac-hPhe-Leu-Ala-LeuVSMe	DMU7SBD	Discovery agent	N.A.	Investigative	[15]
Ac-hPhe-Leu-Gly-LeuVSMe	DMH2SU4	Discovery agent	N.A.	Investigative	[15]
Ac-hPhe-Leu-Phe-LeuVSMe	DMMDJPC	Discovery agent	N.A.	Investigative	[15]
AM-3840	DM2AOF8	Autoimmune diabetes	5A10	Investigative	[4]
BF/PC-18	DMOQEZK	Inflammation	1A00-CA43.1	Investigative	[4]
Cbz-Glu(OtBu)-Ala-LeuVSMe	DM21JVF	Discovery agent	N.A.	Investigative	[15]
Cbz-Ile-hPhe-Ala-LeuVSMe	DMV8CJK	Discovery agent	N.A.	Investigative	[15]
Cbz-Ile-Leu-Ala-LeuVSMe	DMBFLHD	Discovery agent	N.A.	Investigative	[15]
Cbz-Ile-MetO2-Ala-LeuVSMe	DMY4M3J	Discovery agent	N.A.	Investigative	[15]
Cbz-Ile-Phe-Ala-LeuVSMe	DM1OAW3	Discovery agent	N.A.	Investigative	[15]
Cbz-Ile-Pro-Ala-LeuVSMe	DM1KDWE	Discovery agent	N.A.	Investigative	[15]
Cbz-Ile-t-ButylGln-Ala-LeuVSMe	DMGTFON	Discovery agent	N.A.	Investigative	[15]
Cbz-Ile-t-ButylhomoGlu-Ala-LeuVSMe	DMNKC9J	Discovery agent	N.A.	Investigative	[15]
Clik60	DM9WUHD	Discovery agent	N.A.	Investigative	[16]
E-64	DMMOPAK	Discovery agent	N.A.	Investigative	[17]
Fsn-0503	DM2KUEV	Solid tumour/cancer	2A00-2F9Z	Investigative	[4]
Fucose	DMAHMSV	N. A.	N. A.	Investigative	[18]
GNF-PF-5434	DMP9AIH	Discovery agent	N.A.	Investigative	[19]
JNJ-10329670	DMBRJ3C	Autoimmune diabetes	5A10	Investigative	[4]
L-873724	DMUP516	Asthma	CA23	Investigative	[20]
N-(1-oxobutan-2-yl)-3-(trifluoromethyl)benzamide	DMI1HBR	Discovery agent	N.A.	Investigative	[21]
N-(2-naphthylsulfonyl)-glycyl-glycine-nitrile	DMF5N4O	Discovery agent	N.A.	Investigative	[22]
N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile	DMUJS4Y	Discovery agent	N.A.	Investigative	[22]
N-(benzyloxycarbonyl)-leucyl-glycine-nitrile	DMR18YI	Discovery agent	N.A.	Investigative	[22]
N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile	DMJ0S5C	Discovery agent	N.A.	Investigative	[22]
N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile	DMXYQWG	Discovery agent	N.A.	Investigative	[22]
N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile	DM3I0WZ	Discovery agent	N.A.	Investigative	[22]
N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile	DMGF4XC	Discovery agent	N.A.	Investigative	[22]
N-(tert-butoxycarbonyl)-norvalyl-glycine-nitrile	DMOP5N7	Discovery agent	N.A.	Investigative	[22]
N-(tert-butoxycarbonyl)-tyrosyl-glycine-nitrile	DMP9JVT	Discovery agent	N.A.	Investigative	[22]
N-(tert-butoxycarbonyl)-valyl-glycine-nitrile	DMUQBOP	Discovery agent	N.A.	Investigative	[22]
N-acetyl-phenylalanyl-glycine-nitrile	DME8O69	Discovery agent	N.A.	Investigative	[22]
N-benzoyl-phenylalanyl-glycine-nitrile	DMRJ4B1	Discovery agent	N.A.	Investigative	[22]
P2,P3 Ketoamide derivative	DMETL3Z	Discovery agent	N.A.	Investigative	[23]
PMID22686657C(R)-26	DM19D7G	Discovery agent	N.A.	Investigative	[24]
VBY- 285	DM8ACIF	Neuropathic pain	8E43.0	Investigative	[4]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] From 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.
• [3] Clinical pipeline report, company report or official report of ViroBay.
• [4] URL: 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).
• [5] Clinical pipeline report, company report or official report of ViroBay.
• [6] Cathepsin B and L inhibitors: a patent review (2010 - present).Expert Opin Ther Pat. 2017 Jun;27(6):643-656.
• [7] An updated patent review of calpain inhibitors (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):17-31.
• [8] Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional se... J Med Chem. 2005 Dec 1;48(24):7535-43.
• [9] Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming. Ann Rheum Dis. 2015 Feb;74(2):452-63.
• [10] Phase I clinical trial for cathepsin S inhibitor for psoriasis begins. Celera Genomics. 2005.
• [11] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [12] Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1524-7.
• [13] 2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4447-50.
• [14] 4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4507-10.
• [15] 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 c... J Med Chem. 2006 May 18;49(10):2953-68.
• [16] Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J Clin Invest. 2002 Aug;110(3):361-9.
• [17] Baculoviral expression and characterization of rodent cathepsin S. Protein Expr Purif. 2001 Oct;23(1):45-54.
• [18] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [19] Substrate optimization for monitoring cathepsin C activity in live cells. Bioorg Med Chem. 2009 Feb 1;17(3):1064-70.
• [20] The identification of potent, selective, and bioavailable cathepsin S inhibitors. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4929-33.
• [21] Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors. Bioorg Med Chem Lett. 2010 Dec 1;20(23):6890-4.
• [22] Interaction of papain-like cysteine proteases with dipeptide-derived nitriles. J Med Chem. 2005 Dec 1;48(24):7688-707.
• [23] Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions. Bioorg Med Chem Lett. 2004 Oct 4;14(19):4897-902.
• [24] Selective nitrile inhibitors to modulate the proteolytic synergism of cathepsins S and F. J Med Chem. 2012 Jun 28;55(12):5982-6.