Target Information
| Target General Information | Top | |||||
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| Target ID |
T68290
(Former ID: TTDC00067)
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| Target Name |
Cathepsin S (CTSS)
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| Synonyms |
Cysteine protease cathepsin S
Click to Show/Hide
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| Gene Name |
CTSS
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 7 Target-related Diseases | + | ||||
| 1 | Autoimmune disease [ICD-11: 4A40-4A45] | |||||
| 2 | Sjogren syndrome [ICD-11: 4A43] | |||||
| 3 | Coeliac disease [ICD-11: DA95] | |||||
| 4 | Crohn disease [ICD-11: DD70] | |||||
| 5 | Diabetes mellitus [ICD-11: 5A10] | |||||
| 6 | General pain disorder [ICD-11: 8E43] | |||||
| 7 | Pain [ICD-11: MG30-MG3Z] | |||||
| 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.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.22.27
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| Sequence |
MKRLVCVLLVCSSAVAQLHKDPTLDHHWHLWKKTYGKQYKEKNEEAVRRLIWEKNLKFVM
LHNLEHSMGMHSYDLGMNHLGDMTSEEVMSLMSSLRVPSQWQRNITYKSNPNRILPDSVD WREKGCVTEVKYQGSCGACWAFSAVGALEAQLKLKTGKLVSLSAQNLVDCSTEKYGNKGC NGGFMTTAFQYIIDNKGIDSDASYPYKAMDQKCQYDSKYRAATCSKYTELPYGREDVLKE AVANKGPVSVGVDARHPSFFLYRSGVYYEPSCTQNVNHGVLVVGYGDLNGKEYWLVKNSW GHNFGEEGYIRMARNKGNHCGIASFPSYPEI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T56VPC | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
| 1 | RG7625 | Drug Info | Phase 2 | Autoimmune disease | [1] | |
| 2 | SAR-114137 | Drug Info | Phase 1 | Pain | [2] | |
| 3 | VBY- 036 | Drug Info | Phase 1 | Neuropathic pain | [3] | |
| 4 | VBY- 891 | Drug Info | Phase 1 | Autoimmune diabetes | [4] | |
| 5 | VBY-129 | Drug Info | Phase 1 | Autoimmune diabetes | [5] | |
| Patented Agent(s) | [+] 8 Patented Agents | + | ||||
| 1 | Oxotetrahydro-2-H-furo[3.2-b]pyrrol-4(5-H)-yl derivative 1 | Drug Info | Patented | Pain | [6] | |
| 2 | Phenylalanine derivative 1 | Drug Info | Patented | Glioma | [6] | |
| 3 | PMID27998201-Compound-12 | Drug Info | Patented | Cancer related pain | [6] | |
| 4 | PMID27998201-Compound-15 | Drug Info | Patented | Pain | [6] | |
| 5 | PMID27998201-Compound-17 | Drug Info | Patented | Hair loss | [6] | |
| 6 | PMID27998201-Compound-5 | Drug Info | Patented | Cirrhosis | [6] | |
| 7 | PMID27998201-Compound-7 | Drug Info | Patented | Abdominal aortic aneurysm | [6] | |
| 8 | PMID27998201-Compound-9 | Drug Info | Patented | Rheumatoid arthritis | [6] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | RG-7236 | Drug Info | Discontinued in Phase 1 | Cardiovascular disease | [7] | |
| 2 | CRA-028129 | Drug Info | Terminated | Psoriatic disorder | [10] | |
| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | L-006235-1 | Drug Info | Preclinical | Osteoarthritis | [8] | |
| 2 | RO5461111 | Drug Info | Preclinical | Systemic lupus erythematosus | [9] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | RG7625 | Drug Info | [1] | |||
| Inhibitor | [+] 57 Inhibitor drugs | + | ||||
| 1 | SAR-114137 | Drug Info | [2] | |||
| 2 | VBY- 036 | Drug Info | [11] | |||
| 3 | VBY-129 | Drug Info | [13] | |||
| 4 | Oxotetrahydro-2-H-furo[3.2-b]pyrrol-4(5-H)-yl derivative 1 | Drug Info | [6] | |||
| 5 | Phenylalanine derivative 1 | Drug Info | [6] | |||
| 6 | PMID25399719-Compound-17 | Drug Info | [14] | |||
| 7 | PMID27998201-Compound-12 | Drug Info | [6] | |||
| 8 | PMID27998201-Compound-15 | Drug Info | [6] | |||
| 9 | PMID27998201-Compound-17 | Drug Info | [6] | |||
| 10 | PMID27998201-Compound-5 | Drug Info | [6] | |||
| 11 | PMID27998201-Compound-6 | Drug Info | [6] | |||
| 12 | PMID27998201-Compound-7 | Drug Info | [6] | |||
| 13 | PMID27998201-Compound-9 | Drug Info | [6] | |||
| 14 | RG-7236 | Drug Info | [12] | |||
| 15 | L-006235-1 | Drug Info | [15] | |||
| 16 | RO5461111 | Drug Info | [9] | |||
| 17 | CRA-028129 | Drug Info | [16] | |||
| 18 | 2-[(2',3',4'-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL | Drug Info | [17] | |||
| 19 | 4-cycloheptyl-6-propylpyrimidine-2-carbonitrile | Drug Info | [18] | |||
| 20 | 4-cyclooctyl-6-propylpyrimidine-2-carbonitrile | Drug Info | [18] | |||
| 21 | 4-propyl-6-m-tolylpyrimidine-2-carbonitrile | Drug Info | [19] | |||
| 22 | 6-(3-(trifluoromethyl)phenyl)picolinonitrile | Drug Info | [20] | |||
| 23 | Ac-hPhe-Leu-Ala-LeuVSMe | Drug Info | [21] | |||
| 24 | Ac-hPhe-Leu-Gly-LeuVSMe | Drug Info | [21] | |||
| 25 | Ac-hPhe-Leu-Phe-LeuVSMe | Drug Info | [21] | |||
| 26 | AM-3840 | Drug Info | [12] | |||
| 27 | BF/PC-18 | Drug Info | [12] | |||
| 28 | Cbz-Glu(OtBu)-Ala-LeuVSMe | Drug Info | [21] | |||
| 29 | Cbz-Ile-hPhe-Ala-LeuVSMe | Drug Info | [21] | |||
| 30 | Cbz-Ile-Leu-Ala-LeuVSMe | Drug Info | [21] | |||
| 31 | Cbz-Ile-MetO2-Ala-LeuVSMe | Drug Info | [21] | |||
| 32 | Cbz-Ile-Phe-Ala-LeuVSMe | Drug Info | [21] | |||
| 33 | Cbz-Ile-Pro-Ala-LeuVSMe | Drug Info | [21] | |||
| 34 | Cbz-Ile-t-ButylGln-Ala-LeuVSMe | Drug Info | [21] | |||
| 35 | Cbz-Ile-t-ButylhomoGlu-Ala-LeuVSMe | Drug Info | [21] | |||
| 36 | Clik60 | Drug Info | [22] | |||
| 37 | E-64 | Drug Info | [23] | |||
| 38 | Fucose | Drug Info | [24] | |||
| 39 | GNF-PF-5434 | Drug Info | [25] | |||
| 40 | JNJ-10329670 | Drug Info | [12] | |||
| 41 | L-873724 | Drug Info | [26] | |||
| 42 | N-(1-oxobutan-2-yl)-3-(trifluoromethyl)benzamide | Drug Info | [27] | |||
| 43 | N-(2-naphthylsulfonyl)-glycyl-glycine-nitrile | Drug Info | [28] | |||
| 44 | N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile | Drug Info | [28] | |||
| 45 | N-(benzyloxycarbonyl)-leucyl-glycine-nitrile | Drug Info | [28] | |||
| 46 | N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile | Drug Info | [28] | |||
| 47 | N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile | Drug Info | [28] | |||
| 48 | N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile | Drug Info | [28] | |||
| 49 | N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile | Drug Info | [28] | |||
| 50 | N-(tert-butoxycarbonyl)-norvalyl-glycine-nitrile | Drug Info | [28] | |||
| 51 | N-(tert-butoxycarbonyl)-tyrosyl-glycine-nitrile | Drug Info | [28] | |||
| 52 | N-(tert-butoxycarbonyl)-valyl-glycine-nitrile | Drug Info | [28] | |||
| 53 | N-acetyl-phenylalanyl-glycine-nitrile | Drug Info | [28] | |||
| 54 | N-benzoyl-phenylalanyl-glycine-nitrile | Drug Info | [28] | |||
| 55 | P2,P3 Ketoamide derivative | Drug Info | [29] | |||
| 56 | PMID22686657C(R)-26 | Drug Info | [30] | |||
| 57 | VBY- 285 | Drug Info | [12] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | VBY- 891 | Drug Info | [12] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 2-[(2',3',4'-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL | Ligand Info | |||||
| Structure Description | The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method | PDB:2OP3 | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | No | [31] |
| PDB Sequence |
LPDSVDWREK
10 GCVTEVKYQG20 SCGACWAFSA30 VGALEAQLKL40 KTGKLVSLSA50 QNLVDCSTEK 60 YGNKGCNGGF70 MTTAFQYIID80 NKGIDSDASY90 PYKAMDQKCQ100 YDSKYRAATC 110 SKYTELPYGR120 EDVLKEAVAN130 KGPVSVGVDA140 RHPSFFLYRS150 GVYYEPSCTQ 160 NVNHGVLVVG170 YGDLNGKEYW180 LVKNSWGHNF190 GEEGYIRMAR200 NKGNHCGIAS 210 FPSYPEI
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| Ligand Name: N-[(8r)-8-(Benzoylamino)-5,6,7,8-Tetrahydronaphthalen-2-Yl]-4-Methylpiperazine-1-Carboxamide | Ligand Info | |||||
| Structure Description | Crystal Structure of Human Cathepsin S Bound to a Non-covalent Inhibitor | PDB:4P6E | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [32] |
| PDB Sequence |
ILPDSVDWRE
9 KGCVTEVKYQ19 GSCGACWAFS29 AVGALEAQLK39 LKTGKLVSLS49 AQNLVDCSTE 59 KYGNKGCNGG69 FMTTAFQYII79 DNKGIDSDAS89 YPYKAMDQKC99 QYDSKYRAAT 109 CSKYTELPYG119 REDVLKEAVA129 NKGPVSVGVD139 ARHPSFFLYR149 SGVYYEPSCT 159 QNVNHGVLVV169 GYGDLNGKEY179 WLVKNSWGHN189 FGEEGYIRMA199 RNKGNHCGIA 209 SFPSYPEIE
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Putative inactive cathepsin L-like protein CTSL3P (CTSL3P) | 39.474 (45/114) | 1.15E-09 | |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Lysosome | hsa04142 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Phagosome | hsa04145 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Apoptosis | hsa04210 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Antigen processing and presentation | hsa04612 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 6.04E-06 |
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| Closeness centrality | 1.82E-01 | Radiality | 1.30E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 1.00E+01 | Topological coefficient | 4.20E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | Lysosome | |||||
| 2 | Phagosome | |||||
| 3 | Antigen processing and presentation | |||||
| 4 | Tuberculosis | |||||
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | Leptin Signaling Pathway | |||||
| 2 | IL2 Signaling Pathway | |||||
| Reactome | [+] 5 Reactome Pathways | + | ||||
| 1 | Endosomal/Vacuolar pathway | |||||
| 2 | Degradation of the extracellular matrix | |||||
| 3 | Trafficking and processing of endosomal TLR | |||||
| 4 | Assembly of collagen fibrils and other multimeric structures | |||||
| 5 | MHC class II antigen presentation | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Class I MHC mediated antigen processing & presentation | |||||
| 2 | Trafficking and processing of endosomal TLR | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 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. | |||||
| REF 3 | ClinicalTrials.gov (NCT01892891) Safety Study of VBY-036 in Healthy Volunteers After 7 Days of Oral Dosing. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.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 5 | Clinical pipeline report, company report or official report of ViroBay. | |||||
| REF 6 | Cathepsin B and L inhibitors: a patent review (2010 - present).Expert Opin Ther Pat. 2017 Jun;27(6):643-656. | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033628) | |||||
| REF 8 | Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. Bone. 2012 Jun;50(6):1250-9. | |||||
| REF 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. | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022029) | |||||
| REF 11 | Clinical pipeline report, company report or official report of ViroBay. | |||||
| REF 12 | 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). | |||||
| REF 13 | Clinical pipeline report, company report or official report of ViroBay. | |||||
| REF 14 | An updated patent review of calpain inhibitors (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):17-31. | |||||
| REF 15 | 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. | |||||
| REF 16 | Phase I clinical trial for cathepsin S inhibitor for psoriasis begins. Celera Genomics. 2005. | |||||
| REF 17 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 18 | 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. | |||||
| REF 19 | 2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4447-50. | |||||
| REF 20 | 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. | |||||
| REF 21 | 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. | |||||
| REF 22 | Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. J Clin Invest. 2002 Aug;110(3):361-9. | |||||
| REF 23 | Baculoviral expression and characterization of rodent cathepsin S. Protein Expr Purif. 2001 Oct;23(1):45-54. | |||||
| REF 24 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 25 | Substrate optimization for monitoring cathepsin C activity in live cells. Bioorg Med Chem. 2009 Feb 1;17(3):1064-70. | |||||
| REF 26 | The identification of potent, selective, and bioavailable cathepsin S inhibitors. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4929-33. | |||||
| REF 27 | Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors. Bioorg Med Chem Lett. 2010 Dec 1;20(23):6890-4. | |||||
| REF 28 | Interaction of papain-like cysteine proteases with dipeptide-derived nitriles. J Med Chem. 2005 Dec 1;48(24):7688-707. | |||||
| REF 29 | 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. | |||||
| REF 30 | Selective nitrile inhibitors to modulate the proteolytic synergism of cathepsins S and F. J Med Chem. 2012 Jun 28;55(12):5982-6. | |||||
| REF 31 | Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode. J Med Chem. 2007 May 31;50(11):2693-9. | |||||
| REF 32 | Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm. ACS Med Chem Lett. 2014 Aug 27;5(10):1138-42. | |||||
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