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cathepsin C

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Target id: 2344

Nomenclature: cathepsin C

Family: C1: Papain

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 463 11q14.2 CTSC cathepsin C
Mouse - 462 7 D3 Ctsc cathepsin C
Rat - 462 1q32 Ctsc cathepsin C
Previous and Unofficial Names Click here for help
CATC | cathepsin J | dipeptidyl peptidase 1 | dipeptidyl transferase | DPP1 | PALS | PLS
Database Links Click here for help
Specialist databases
MEROPS C01.070 (Hs)
Other databases
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 3.4.14.1

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
brensocatib Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 8.6 pKd 1
pKd 8.6 (Kd 2.5x10-9 M) [1]
Description: Surface plasmon resonance direct binding assay
compound 3d [PMID: 3941405] Small molecule or natural product Hs Inhibition 5.6 pKi 4
pKi 5.6 (Ki 2.7x10-6 M) [4]
brensocatib Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 8.4 pIC50 1
pIC50 8.4 (IC50 3.98x10-9 M) [1]
Description: In vitro enzyme assay
IcatCXPZ-01 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.8 pIC50 3
pIC50 7.8 (IC50 1.5x10-8 M) [3]
brensocatib Small molecule or natural product Immunopharmacology Ligand Rn Inhibition 7.7 pIC50 1
pIC50 7.7 (IC50 1.99x10-8 M) [1]
Description: In vitro enzyme assay
brensocatib Small molecule or natural product Immunopharmacology Ligand Mm Inhibition 7.6 pIC50 1
pIC50 7.6 (IC50 2.51x10-8 M) [1]
Description: In vitro enzyme assay
View species-specific inhibitor tables
Immunopharmacology Comments
Cathepsin C (CatC) is a lysosomal cysteine protease that is constitutively expressed at high levels in lung, kidney, liver and spleen. As well as activity in lysosomal protein degradation, cathepsin C also plays a key role in the activation of granule serine proteases in cytotoxic T cells, natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G, neutrophil elastase, proteinase 3). Dysregulated activation of neutrophil elastase at inflammatory sites induces the release of pro-inflammatoy mediators and can lead to acute tissue injury. This mechanism is recognised as causing lung damage in neutrophil driven conditions such as asthma and COPD, and has driven the pharmaceutical industry to search for cathepsin C inhibitors with clinical utility (e.g. brensocatib; formerly AZD7986 and INS1007).

SARS-CoV-2 and COVID-19: CatC has been proposed as a drug target to combat ARDS-associated inflammatory lung damage in patients with severe COVID-19. In this setting CatC inhibitors would be expected to protect the lungs from ARDS by reducing the observed virally-induced hyperinflammation that leads to diffuse alveolar collapse and pulmonary tissue damage [2].
Cell Type Associations
Immuno Cell Type:  Mast cells
Immuno Cell Type:  T cells
Cell Ontology Term:   mature CD8 single-positive thymocyte (CL:0002437)
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   mature neutrophil (CL:0000096)
neutrophil (CL:0000775)
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   natural killer cell (CL:0000623)
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0043312 neutrophil degranulation TAS
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GO:1903980 positive regulation of microglial cell activation IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:1903980 positive regulation of microglial cell activation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0043312 neutrophil degranulation TAS
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GO:1903980 positive regulation of microglial cell activation IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0001913 T cell mediated cytotoxicity IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0001913 T cell mediated cytotoxicity IEA
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Haim-Munk syndrome
OMIM: 245010
Orphanet: ORPHA2342
Disease:  Papillon-Lefevre syndrome
Synonyms: Papillon-Lefevre disease [Disease Ontology: DOID:3389]
Disease Ontology: DOID:3389
OMIM: 245000
Orphanet: ORPHA678
Disease:  Periodontitis, aggressive, 1
Synonyms: Aggressive periodontitis [Disease Ontology: DOID:1474]
Disease Ontology: DOID:1474
OMIM: 170650

References

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1. Doyle K, Lönn H, Käck H, Van de Poël A, Swallow S, Gardiner P, Connolly S, Root J, Wikell C, Dahl G et al.. (2016) Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986). J. Med. Chem., 59 (20): 9457-9472. [PMID:27690432]

2. Korkmaz B, Lesner A, Marchand-Adam S, Moss C, Jenne DE. (2020) Lung Protection by Cathepsin C Inhibition: A New Hope for COVID-19 and ARDS?. J Med Chem, [Epub ahead of print]. [PMID:32692176]

3. Korkmaz B, Lesner A, Wysocka M, Gieldon A, Håkansson M, Gauthier F, Logan DT, Jenne DE, Lauritzen C, Pedersen J. (2019) Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C. Biochem. Pharmacol., 164: 349-367. [PMID:30978322]

4. Thompson SA, Andrews PR, Hanzlik RP. (1986) Carboxyl-modified amino acids and peptides as protease inhibitors. J. Med. Chem., 29 (1): 104-11. [PMID:3941405]

How to cite this page

C1: Papain: cathepsin C. Last modified on 12/08/2020. Accessed on 25/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2344.