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cathepsin S

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2353

Nomenclature: cathepsin S

Family: C1: Papain

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 331 1q21.3 CTSS cathepsin S
Mouse - 340 3 40.74 cM Ctss cathepsin S
Rat - 330 2q34 Ctss cathepsin S
Previous and Unofficial Names Click here for help
Cat S
Database Links Click here for help
Specialist databases
MEROPS C01.034 (Hs)
Other databases
Alphafold P25774 (Hs), O70370 (Mm), Q02765 (Rn)
BRENDA 3.4.22.27
ChEMBL Target CHEMBL2954 (Hs), CHEMBL4098 (Mm), CHEMBL1075217 (Rn)
Ensembl Gene ENSG00000163131 (Hs), ENSMUSG00000038642 (Mm), ENSRNOG00000021157 (Rn)
Entrez Gene 1520 (Hs), 13040 (Mm), 50654 (Rn)
Human Protein Atlas ENSG00000163131 (Hs)
KEGG Enzyme 3.4.22.27
KEGG Gene hsa:1520 (Hs), mmu:13040 (Mm), rno:50654 (Rn)
OMIM 116845 (Hs)
Pharos P25774 (Hs)
RefSeq Nucleotide NM_001199739 (Hs), NM_004079 (Hs), NM_001267695 (Mm), NM_017320 (Rn)
RefSeq Protein NP_004070 (Hs), NP_001186668 (Hs), NP_001254624 (Mm), NP_059016 (Rn)
UniProtKB P25774 (Hs), O70370 (Mm), Q02765 (Rn)
Wikipedia CTSS (Hs)
Enzyme Reaction Click here for help
EC Number: 3.4.22.27

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
VBY-825 Small molecule or natural product Mm Inhibition 10.4 pKi 1
⤷ pKi 10.4 (Ki 4x10-11 M) [1]
VBY-825 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.9 pKi 1
⤷ pKi 9.9 (Ki 1.3x10-10 M) [1]
compound (R)-26 [PMID: 22686657] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.3 pKi 2
⤷ pKi 9.3 (Ki 5.5x10-10 M) [2]
VBY-825 Small molecule or natural product Rn Inhibition 9.1 pKi 1
⤷ pKi 9.1 (Ki 7.7x10-10 M) [1]
K11777 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.7 pKi 5
⤷ pKi 8.7 (Ki 2x10-9 M) [5]
petesicatib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 10.0 pIC50 8
⤷ pIC50 10.0 (IC50 1x10-10 M) [8]
petesicatib Small molecule or natural product Immunopharmacology Ligand Mm Inhibition 9.5 pIC50 8
⤷ pIC50 9.5 (IC50 3x10-10 M) [8]
compound 4d [PMID: 38746883] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pIC50 7
⤷ pIC50 9.1 (IC50 7x10-10 M) [7]
LHVS Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.0 pIC50 6
⤷ pIC50 9.0 (IC50 1x10-9 M) [6]
odanacatib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 3
⤷ pIC50 7.2 (IC50 6x10-8 M) [3]
View species-specific inhibitor tables
Immunopharmacology Comments
Cathepsin S is expressed in the lysosome of antigen presenting cells (dendritic cells, B-cells and macrophages) where it processes the invariant chain-MHC-II complex (a chaperone protein that prevents premature peptide loading) inside antigen presenting cells and in this way controls antigen presentation. Due to this role in antigen presentation, inhibition of cathepsin S is expected to cause immunosuppression [9]. This enzyme is also a central pathomechanism in autoimmune diseases. Consequently, cathepsin S inhibitors are being investigated for clinical efficacy in autoimmune conditions. Roche's cathepsin S inhibitor petesicatib (RO5459072 or RG7625) completed Phase 2 clinical evaluation in Sjögren's syndrome (NCT02701985) and Phase 1 in celiac disease (NCT02679014), but there are no active clinical trials registered with ClinicalTrials.gov.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Antigen presentation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
General Comments
Cathepsin S, is a lysosomal cysteine protease, whch plays an important role in antigen presentation. Selective cathepsin S inhibitors are being developed for their therapeutic potential in autoimmune disorders, atherosclerosis, osteoporosis, osteoarthritis and cancer [4].

References

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1. Elie BT, Gocheva V, Shree T, Dalrymple SA, Holsinger LJ, Joyce JA. (2010) Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model. Biochimie, 92 (11): 1618-24. [PMID:20447439]

2. Frizler M, Schmitz J, Schulz-Fincke AC, Gütschow M. (2012) Selective nitrile inhibitors to modulate the proteolytic synergism of cathepsins S and F. J Med Chem, 55 (12): 5982-6. [PMID:22686657]

3. Gauthier JY, Chauret N, Cromlish W, Desmarais S, Duong le T, Falgueyret JP, Kimmel DB, Lamontagne S, Léger S, LeRiche T et al.. (2008) The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett, 18 (3): 923-8. [PMID:18226527]

4. Lee-Dutra A, Wiener DK, Sun S. (2011) Cathepsin S inhibitors: 2004-2010. Expert Opin Ther Pat, 21 (3): 311-37. [PMID:21342054]

5. Mellott DM, Tseng CT, Drelich A, Fajtová P, Chenna BC, Kostomiris DH, Hsu J, Zhu J, Taylor ZW, Kocurek KI et al.. (2021) A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells. ACS Chem Biol, 16 (4): 642-650. [PMID:33787221]

6. Méthot N, Rubin J, Guay D, Beaulieu C, Ethier D, Reddy TJ, Riendeau D, Percival MD. (2007) Inhibition of the activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing. J Biol Chem, 282 (29): 20836-46. [PMID:17535802]

7. Previti S, Ettari R, Calcaterra E, Roggia M, Natale B, Weldert AC, Müller-Ruttloff C, Salisch F, Irto A, Cigala RM et al.. (2024) Identification of Dual Inhibitors Targeting Main Protease (Mpro) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents. ACS Med Chem Lett, 15 (5): 602-609. [PMID:38746883]

8. Tato M, Kumar SV, Liu Y, Mulay SR, Moll S, Popper B, Eberhard JN, Thomasova D, Rufer AC, Gruner S et al.. (2017) Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury. Sci Rep, 7 (1): 2775. [PMID:28584258]

9. Thurmond RL, Sun S, Karlsson L, Edwards JP. (2005) Cathepsin S inhibitors as novel immunomodulators. Curr Opin Investig Drugs, 6 (5): 473-82. [PMID:15912960]

How to cite this page

C1: Papain: cathepsin S. Last modified on 15/05/2024. Accessed on 16/01/2025. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2353.