CTSC

Summary

CTSC (cathepsin C, HGNC:2528) is a protein-coding gene on chromosome 11q14.2, encoding Dipeptidyl peptidase 1 (P53634). Thiol protease.

This gene encodes a member of the peptidase C1 family and lysosomal cysteine proteinase that appears to be a central coordinator for activation of many serine proteinases in cells of the immune system. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate heavy and light chains that form a disulfide-linked dimer. A portion of the propeptide acts as an intramolecular chaperone for the folding and stabilization of the mature enzyme. This enzyme requires chloride ions for activity and can degrade glucagon. Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre syndrome, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis.

Source: NCBI Gene 1075 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Papillon-Lefevre disease (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 543 total — 65 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001814

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2528
Approved symbol	CTSC
Name	cathepsin C
Location	11q14.2
Locus type	gene with protein product
Status	Approved
Aliases	DPP1
Ensembl gene	ENSG00000109861
Ensembl biotype	protein_coding
OMIM	602365
Entrez	1075

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 19 protein_coding, 11 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000227266, ENST00000393301, ENST00000524463, ENST00000527018, ENST00000528020, ENST00000529974, ENST00000533865, ENST00000533897, ENST00000534131, ENST00000676529, ENST00000676612, ENST00000677106, ENST00000677208, ENST00000677468, ENST00000677661, ENST00000677796, ENST00000677802, ENST00000677877, ENST00000677976, ENST00000678065, ENST00000678395, ENST00000678464, ENST00000678506, ENST00000678520, ENST00000678554, ENST00000678664, ENST00000678915, ENST00000679032, ENST00000679199, ENST00000679224, ENST00000679297, ENST00000880823, ENST00000880824, ENST00000880825, ENST00000934339, ENST00000934340, ENST00000934341

RefSeq mRNA: 3 — MANE Select: NM_001814 NM_001114173, NM_001814, NM_148170

CCDS: CCDS31654, CCDS44693, CCDS8282

Canonical transcript exons

ENST00000227266 — 7 exons

Exon	Start	End
ENSE00000743349	88296133	88296264
ENSE00000743350	88300530	88300645
ENSE00000743351	88309163	88309318
ENSE00000842724	88293592	88294508
ENSE00002140483	88337501	88337736
ENSE00003481008	88334937	88335082
ENSE00003489208	88312388	88312554

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 212.4070 / max 3516.2641, expressed in 1816 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121771	169.4225	1814
121772	23.7106	1793
121770	18.7258	1746
121773	0.4795	261
121774	0.0452	18
121775	0.0135	8
121776	0.0099	7

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
palpebral conjunctiva	UBERON:0001812	99.78	gold quality
epithelium of nasopharynx	UBERON:0001951	99.25	gold quality
nasopharynx	UBERON:0001728	99.24	gold quality
stromal cell of endometrium	CL:0002255	99.19	gold quality
gall bladder	UBERON:0002110	99.01	gold quality
bronchial epithelial cell	CL:0002328	98.76	gold quality
vermiform appendix	UBERON:0001154	98.76	gold quality
lymph node	UBERON:0000029	98.71	gold quality
rectum	UBERON:0001052	98.62	gold quality
monocyte	CL:0000576	98.58	gold quality
granulocyte	CL:0000094	98.53	gold quality
leukocyte	CL:0000738	98.52	gold quality
epithelium of bronchus	UBERON:0002031	98.52	gold quality
bronchus	UBERON:0002185	98.51	gold quality
mononuclear cell	CL:0000842	98.49	gold quality
caecum	UBERON:0001153	98.39	gold quality
upper lobe of left lung	UBERON:0008952	98.20	gold quality
spleen	UBERON:0002106	98.16	gold quality
upper lobe of lung	UBERON:0008948	98.16	gold quality
parotid gland	UBERON:0001831	98.02	gold quality
lung	UBERON:0002048	98.02	gold quality
decidua	UBERON:0002450	98.00	gold quality
right lung	UBERON:0002167	97.95	gold quality
eye	UBERON:0000970	97.76	gold quality
nasal cavity mucosa	UBERON:0001826	97.62	gold quality
nephron tubule	UBERON:0001231	97.61	gold quality
lower lobe of lung	UBERON:0008949	97.61	gold quality
omental fat pad	UBERON:0010414	97.49	gold quality
peritoneum	UBERON:0002358	97.48	gold quality
blood	UBERON:0000178	97.46	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-MTAB-10855	yes	3902.69
E-MTAB-10485	yes	2449.14
E-MTAB-9906	yes	2058.98
E-GEOD-114530	yes	2028.76
E-GEOD-124472	yes	1635.62
E-CURD-120	yes	1486.83
E-MTAB-7037	yes	591.52
E-HCAD-1	yes	93.30
E-CURD-122	yes	68.85
E-CURD-114	yes	61.58
E-HCAD-10	yes	60.40
E-MTAB-6701	yes	50.80
E-CURD-46	yes	41.94
E-HCAD-11	yes	41.27
E-MTAB-10287	yes	22.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CEBPD

miRNA regulators (miRDB)

22 targeting CTSC, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-5681A	97.99	67.17	1658

Literature-anchored findings (GeneRIF, showing 40)

• Sequencing of the mutant cathepsin C transcript revealed that it lacked exon 3, resulting in a frameshift and introduction of a premature termination codon in Papillon-Lefevre syndrome. (PMID:11914041)
• Selective inhibition prevents the partial processing of procaspase-3 in CD3-activated human CD8(+) T lymphocytes (PMID:12080079)
• Identification of a novel cathepsin C mutation (p.W185X) in a Brazilian kindred with Papillon-Lefevre syndrome. (PMID:12083812)
• All Papillon-Lefevre syndrome affected individuals from three Indian families showed three novel homozygous nonsense mutations in CTSC. (PMID:12857359)
• Three novel CTSC missense mutations found in 21 Papillon-Lefevre syndrome families, and a complete loss of CTSC function appears to be necessary for the manifestation of this phenotype. (PMID:14974080)
• homozygous deletion of 7 nucelotides in exon 4, creating a premature stop codon 11 amino acids downstream; 2 heterozygous missense mutations in exon 7: 1) substitution of leucine by arginine; 2)changing tryptophan to serine. (PMID:15111626)
• This report describes the apparent reason why the study of the natural history of human patients with Papillon-Lefevre syndrome has failed to detect a generalized T cell immunodeficiency phenotype. (PMID:15585850)
• DPP-I may play a role in converting endogenous beta-melanocortin MSH(5-22) to more potent peptides that regulate energy homeostasis in the hypothalamus. (PMID:15985311)
• The structure of the inhibitor complex provides an explanation of the substrate specificity of hDPPI, and gives a background for the design of new inhibitors. (PMID:17020538)
• inhibition of activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing (PMID:17535802)
• Novel mutations in two Chinese patients with Papillon-Lefevre syndrome (PMID:17652201)
• G386R missense mutation and an intragenic deletion spanning exons 3-7 and homozygous splice site mutation, p.A253SfsX30 found in papillon-Lefevre syndrome (PMID:17943190)
• study aimed to identify CTSC mutations in different Papillon-Lefevre phenotypes, including atypical forms and isolated pre-pubertal aggressive periodontitis (PMID:18294227)
• Cathepsin C propeptide interacts with intestinal alkaline phosphatase (IAP) and heat shock cognate protein 70. The propeptide of cathepsin C may stimulate the sorting to the lysosome contributing to the degradation of IAP in Caco-2 cells. (PMID:18307834)
• gene variants contribute to increased susceptibility in generalized aggressive periodontitis (PMID:18809751)
• Mutations of the cathepsin C gene are probably responsible for the phenotype of Papillon-Lefevre syndrome in this family. (PMID:18841559)
• study identified an identical recurrent missense mutation, R272P, in 3 families with Papillon-Lefevre syndrome(PLS); presence of this mutation in families from 2 different geographical areas provides evidence for founder effect for CTSC mutations in PLS (PMID:19816003)
• A novel mutation in the cathepsin C gene is reported in a Pakistani family with Papillon-Lefevre syndrome. (PMID:20236208)
• This report described a novel mutation (c.267-268del)in a family with Brazilian Papillon-Lefevre syndrome and presented a review of all cathepsin C (65) mutations reported to date. (PMID:20359428)
• Two Indian siblings present with Haim Munk syndrome (HMS) and its cardinal features including palmoplantar keratoderma, periodontitis. arachnodactyly, acroosteolysis, onychogryphosis, osteopenia as well as allelic mutation of cathepsin C exon 6 codon. (PMID:21393975)
• Processing of human protryptase in mast cells involves cathepsins L, B, and C. (PMID:21742978)
• The Cathepsin C releases the glycosidases from complexes formed with cathepsin A, and reinstates their activity. (PMID:22532132)
• present a catalytic model derived from the relative rates of the acylation vs deacylation half-reactions of cathepsin C. (PMID:22928782)
• Cathepsin C gene 5’-untranslated region mutation in papillon-lefevre syndrome in 4 unrelated families in Slovenia (PMID:23108224)
• The novel loss-of function mutation of CTSC gene (c.203 T > G) found in Papillon-Lefevre Syndrome patients correlated with their diminished enzymatic activity. (PMID:23311634)
• Report novel deletion mutation in CTSC gene in Hungarian family with Papillon-Lefevre syndrome. (PMID:23397598)
• The present account of the 148.621 kb homozygous deletion on chromosome 11 is the first report of a mutational mechanism encompassing the whole CTSC gene. (PMID:23556547)
• CTSC mutations in 5 Iranian families with Papillon-Lefevre syndrome (PLS)analyzed; modeled the protein for mutations found in 2 of them; presence of this mutation provides evidence for founder CTSC mutations in PLS; this P35delL mutation leads to loss of a leucine residue; results indicate the phenotypes in these 2 patients likely due to CTSC mutations (PMID:24374475)
• Papillon-Lefevre syndrome cause by homozygous nonsense mutation of cathepsin C gene. (PMID:24894642)
• cathepsin C in GCF does not seem to have an effect on the pathogenesis of periodontal diseases. (PMID:24949444)
• CatC has a role in the selective tuning of innate and adaptive immune responses, relevant to a chronic immune disease, such as atherosclerosis. (PMID:25395616)
• Results identify a missense mutation in CTSC gene that segregate within a family with Papillon-Lefevre syndrome. (PMID:25799584)
• Mutation screening of the CTSC gene from the two patients revealed the presence of the same homozygous nonsense mutation in Papillon-Lefevre syndrome and Haim-Munk syndromes. Phenotypic variants of the same rare disease caused by mutations of the cathepsin C (CTSC) gene. (PMID:26205983)
• A compound mutation consisting of a large deletion and a nonsense mutation, which provides a new insight in the mutation type of CTSC gene. (PMID:26385525)
• CTSC was associated with albuminuria in type 2 diabetes patients. (PMID:26631737)
• Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases. (PMID:26884336)
• Homozygous mutation 901G>A in exon 7 of CTSC gene is associated with Papillon-Lefevre syndrome. (PMID:27060303)
• CTSC gene missense mutation is responsible for Papillo- Lefevre syndrome in a Turkish family. (PMID:27062382)
• analysis of fluorescent substrates provides a detailed S’ specificity study of cathepsin C (PMID:27746119)
• expression markedly increased in the maternal vascular endothelium in subjects with preeclampsia compared with normal pregnant controls (PMID:28878298)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsc	ENSDARG00000101334
mus_musculus	Ctsc	ENSMUSG00000030560
rattus_norvegicus	Ctsc	ENSRNOG00000016496
caenorhabditis_elegans		WBGENE00000781
caenorhabditis_elegans		WBGENE00000782
caenorhabditis_elegans		WBGENE00000784
caenorhabditis_elegans		WBGENE00000785
caenorhabditis_elegans		WBGENE00013072
caenorhabditis_elegans		WBGENE00013076
caenorhabditis_elegans		WBGENE00013764
caenorhabditis_elegans		WBGENE00016300
caenorhabditis_elegans		WBGENE00016306
caenorhabditis_elegans		WBGENE00019314
caenorhabditis_elegans		WBGENE00019986
caenorhabditis_elegans		WBGENE00022189
caenorhabditis_elegans		WBGENE00044760

Paralogs (12): CTSZ (ENSG00000101160), CTSH (ENSG00000103811), CTSL (ENSG00000135047), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Protein

Protein identifiers

Dipeptidyl peptidase 1 — P53634 (reviewed: P53634)

Alternative names: Cathepsin C, Cathepsin J, Dipeptidyl peptidase I, Dipeptidyl transferase

All UniProt accessions (18): P53634, A0A7I2V2F3, A0A7I2V2Q8, A0A7I2V2V5, A0A7I2V3A2, A0A7I2V3A6, A0A7I2V3M6, A0A7I2V466, A0A7I2V4Z3, A0A7I2V592, A0A7I2V5C5, A0A7I2V5J2, A0A7I2V5L5, A0A7I2V6E3, A0A7I2YQ96, A0A7I2YQT5, H0YCY8, H0YDA2

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease. Has dipeptidylpeptidase activity. Active against a broad range of dipeptide substrates composed of both polar and hydrophobic amino acids. Proline cannot occupy the P1 position and arginine cannot occupy the P2 position of the substrate. Can act as both an exopeptidase and endopeptidase. Activates serine proteases such as elastase, cathepsin G and granzymes A and B.

Subunit / interactions. Tetramer of heterotrimers consisting of exclusion domain, heavy- and light chains.

Subcellular location. Lysosome.

Tissue specificity. Ubiquitous. Highly expressed in lung, kidney and placenta. Detected at intermediate levels in colon, small intestine, spleen and pancreas.

Post-translational modifications. N-glycosylated. While glycosylation at Asn-53, Asn-119 and Asn-276 is mediated by STT3A-containing complexes, glycosylation at Asn-29 is mediated STT3B-containing complexes. In approximately 50% of the complexes the exclusion domain is cleaved at position 58 or 61. The two parts of the exclusion domain are held together by a disulfide bond.

Disease relevance. Papillon-Lefevre syndrome (PLS) [MIM:245000] An autosomal recessive disorder characterized by palmoplantar keratosis and severe periodontitis affecting deciduous and permanent dentitions and resulting in premature tooth loss. The palmoplantar keratotic phenotype vary from mild psoriasiform scaly skin to overt hyperkeratosis. Keratosis also affects other sites such as elbows and knees. The disease is caused by variants affecting the gene represented in this entry. Haim-Munk syndrome (HMS) [MIM:245010] An autosomal recessive disorder characterized by palmoplantar keratosis, onychogryphosis and periodontitis. Additional features are pes planus, arachnodactyly, and acroosteolysis. The disease is caused by variants affecting the gene represented in this entry. Periodontititis, aggressive, 1 (AP1) [MIM:170650] A disease characterized by severe and protracted gingival infections, generalized or localized, leading to tooth loss. Amounts of microbial deposits are generally inconsistent with the severity of periodontal tissue destruction and the progression of attachment and bone loss may be self arresting. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Strongly inhibited by the cysteine peptidase inhibitors mersalyl acid, iodoacetic acid and cystatin. Inhibited by N-ethylmaleimide, Gly-Phe-diazomethane, TLCK, TPCK and, at low pH, by dithiodipyridine. Not inhibited by the serine peptidase inhibitor PMSF, the aminopeptidase inhibitor bestatin, or metal ion chelators.

Cofactor. Binds 1 Cl(-) ion per heavy chain.

Induction. Up-regulated in lymphocytes by IL2/interleukin-2.

Similarity. Belongs to the peptidase C1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P53634-1	1	yes
P53634-2	2
P53634-3	3

RefSeq proteins (3): NP_001107645, NP_001805, NP_680475 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000169	Pept_cys_AS	Active_site
IPR000668	Peptidase_C1A_C	Domain
IPR013128	Peptidase_C1A	Family
IPR014882	CathepsinC_exc	Domain
IPR025660	Pept_his_AS	Active_site
IPR025661	Pept_asp_AS	Active_site
IPR036496	CathepsinC_exc_dom_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR039412	CatC	Domain

Pfam: PF00112, PF08773

Enzyme classification (BRENDA):

• EC 3.4.14.1 — dipeptidyl-peptidase I (BRENDA: 17 organisms, 142 substrates, 224 inhibitors, 37 Km, 26 kcat entries)

Substrate kinetics (BRENDA)

30 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BETA-(2-THIENYL)ALA-BETA-(7-METHOXYCOUMARIN-4-YL	0.0034–0.0052	2
BETA-(2-THIENYL)ALA-BETA-(7-METHOXYCOUMARIN-4-YL	0.0022–0.0032	2
BETA-(2-THIENYL)ALA-BETA-(7-METHOXYCOUMARIN-4-YL	0.0032–0.0052	2
BETA-(2-THIENYL)ALA-PHE-7-AMIDO-4-METHYLCOUMARIN	0.003–0.0036	2
GLY-L-PHE-7-AMIDO-4-METHYLCOUMARIN	0.186–0.194	2
GLY-TRP-METHYL ESTER	0.63–1.5	2
L-SER-L-TYR-7-AMIDO-4-METHYLCOUMARIN	6.4–17	2
ALPHA-ASP-ARG-2-NAPHTHYLAMIDE	0.31	1
ASN1-ANGIOTENSIN II	0.44	1
BENZYLOXYARBONYL-GLY-L-PRO-L-ARG-7-AMIDO-4-METHY	0.028	1
BENZYLOXYCARBONYL-L-LEU-L-ARG-7-AMIDO-4-METHYLCO	0.0023	1
BENZYLOXYCARBONYL-L-PHE-L-ARG-7-AMIDO-4-METHYLCO	0.0065	1
GLUCAGON	0.027	1
GLY-ARG-2-NAPHTHYLAMIDE	0.1	1
GLY-ARG-4-METHOXY-BETA-NAPHTHYLAMIDE	0.14	1

UniProt features (96 total): sequence variant 31, strand 18, helix 11, sequence conflict 6, turn 6, disulfide bond 5, glycosylation site 4, splice variant 4, chain 3, binding site 3, active site 3, signal peptide 1, propeptide 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4OEL	X-RAY DIFFRACTION	1.4
4OEM	X-RAY DIFFRACTION	1.52
6RNI	X-RAY DIFFRACTION	1.54
6RNE	X-RAY DIFFRACTION	1.65
6RN7	X-RAY DIFFRACTION	1.66
3PDF	X-RAY DIFFRACTION	1.85
6IC6	X-RAY DIFFRACTION	1.9
6RN9	X-RAY DIFFRACTION	1.9
2DJF	X-RAY DIFFRACTION	2
6IC5	X-RAY DIFFRACTION	2
6IC7	X-RAY DIFFRACTION	2
2DJG	X-RAY DIFFRACTION	2.05
1K3B	X-RAY DIFFRACTION	2.15
4CDF	X-RAY DIFFRACTION	2.2
4CDD	X-RAY DIFFRACTION	2.35
4CDC	X-RAY DIFFRACTION	2.4
4CDE	X-RAY DIFFRACTION	2.4
6RN6	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53634-F1	90.64	0.80

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 258; 405; 427

Ligand- & substrate-binding residues (3): 347; 302; 304

Disulfide bonds (5): 30–118, 54–136, 255–298, 291–331, 321–337

Glycosylation sites (4): 29, 53, 119, 276

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-2132295	MHC class II antigen presentation
R-HSA-5694530	Cargo concentration in the ER
R-HSA-6798695	Neutrophil degranulation
R-HSA-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification
R-HSA-948021	Transport to the Golgi and subsequent modification

MSigDB gene sets: 594 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, MODULE_172, GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_52, WALLACE_PROSTATE_CANCER_RACE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, MCLACHLAN_DENTAL_CARIES_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, MODULE_151, MODULE_45

GO Biological Process (9): T cell mediated cytotoxicity (GO:0001913), proteolysis (GO:0006508), immune response (GO:0006955), negative regulation of myelination (GO:0031642), obsolete proteolysis involved in protein catabolic process (GO:0051603), obsolete positive regulation of proteolysis involved in protein catabolic process (GO:1903052), positive regulation of microglial cell activation (GO:1903980), positive regulation of apoptotic signaling pathway (GO:2001235), apoptotic process (GO:0006915)

GO Molecular Function (12): cysteine-type endopeptidase activity (GO:0004197), serine-type endopeptidase activity (GO:0004252), cysteine-type peptidase activity (GO:0008234), dipeptidyl-peptidase activity (GO:0008239), peptidase activator activity involved in apoptotic process (GO:0016505), phosphatase binding (GO:0019902), chloride ion binding (GO:0031404), identical protein binding (GO:0042802), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (13): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), lysosome (GO:0005764), endoplasmic reticulum lumen (GO:0005788), centrosome (GO:0005813), membrane (GO:0016020), COPII-coated ER to Golgi transport vesicle (GO:0030134), extracellular matrix (GO:0031012), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
ER to Golgi Anterograde Transport	2
Immune System	2
Adaptive Immune System	1
Innate Immune System	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Post-translational protein modification	1
Metabolism of proteins	1
Asparagine N-linked glycosylation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
apoptotic signaling pathway	2
endopeptidase activity	2
protein binding	2
leukocyte mediated cytotoxicity	1
T cell mediated immunity	1
protein metabolic process	1
immune system process	1
response to stimulus	1
regulation of myelination	1
negative regulation of nervous system process	1
myelination	1
negative regulation of cellular process	1
microglial cell activation	1
positive regulation of macrophage activation	1
positive regulation of neuroinflammatory response	1
regulation of microglial cell activation	1
positive regulation of signal transduction	1
positive regulation of apoptotic process	1
regulation of apoptotic signaling pathway	1
programmed cell death	1
execution phase of apoptosis	1
cysteine-type peptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
exopeptidase activity	1
apoptotic process	1
peptidase activator activity	1
enzyme binding	1
anion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
lytic vacuole	1
endoplasmic reticulum	1
intracellular organelle lumen	1
centriole	1
microtubule organizing center	1

Protein interactions and networks

STRING

2613 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSC	GZMA	P12544	837
CTSC	GLT6D1	Q7Z4J2	753
CTSC	CMA1	P23946	752
CTSC	GZMB	P10144	697
CTSC	CTSG	P08311	673
CTSC	TPSAB1	P15157	658
CTSC	CTSD	P07339	656
CTSC	LGMN	Q99538	646
CTSC	DPP7	Q9UHL4	646
CTSC	LMAN1	P49257	638
CTSC	SPINK5	Q9NQ38	617
CTSC	ING1	Q9UK53	616
CTSC	PRTN3	P15637	599
CTSC	CST7	O76096	595
CTSC	DSG1	Q02413	594

IntAct

51 interactions, top by confidence:

A	B	Type	Score
RBM8A	CASC3	psi-mi:“MI:0914”(association)	0.900
DMWD	CTSC	psi-mi:“MI:0915”(physical association)	0.560
CTSC	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
G3BP1	COX5A	psi-mi:“MI:0914”(association)	0.530
WFDC9	CTSC	psi-mi:“MI:0914”(association)	0.530
CST6	CTSV	psi-mi:“MI:0914”(association)	0.530
CST7	CTSC	psi-mi:“MI:0915”(physical association)	0.400
CTSC	CST7	psi-mi:“MI:0915”(physical association)	0.400
	CTSC	psi-mi:“MI:0915”(physical association)	0.370
Ppp2r1a	CCHCR1	psi-mi:“MI:0914”(association)	0.350
Dctn3		psi-mi:“MI:0914”(association)	0.350
Tuba3a	CCHCR1	psi-mi:“MI:0914”(association)	0.350
Bub1	PEX10	psi-mi:“MI:0914”(association)	0.350
CEP43	CCHCR1	psi-mi:“MI:0914”(association)	0.350
SGO1	ELOC	psi-mi:“MI:0914”(association)	0.350
Nek2	WDR46	psi-mi:“MI:0914”(association)	0.350
Ktn1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SAE1	PQBP1	psi-mi:“MI:0914”(association)	0.350
Smo	METTL8	psi-mi:“MI:0914”(association)	0.350
MAPK8		psi-mi:“MI:0914”(association)	0.350
TBC1D16	CTSC	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
G3BP1	AGPS	psi-mi:“MI:0914”(association)	0.350
POC5	PDHX	psi-mi:“MI:0914”(association)	0.350
CCP110	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCP110	KIF2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (69): CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS), CTSC (Affinity Capture-MS)

ESM2 similar proteins: A0A218QX58, A1BQQ5, A6YPK1, A8XP79, A9QQ26, A9YME1, B0WQ10, B8UU78, C1IBY2, C1IBY3, C8YJ98, C8YJ99, C8YJA0, C8YJA1, C8YJA2, C8YJG5, E0XKJ8, F8QQG5, G3CJR9, G5ECE8, G5EDW5, H2A0L2, H2A0L3, O16977, O55159, O97578, P16422, P34393, P53634, P80067, P85840, P86953, P86954, P97821, P98061, Q18594, Q1WER1, Q21181, Q3T0L5, Q3ZCJ8

Diamond homologs: A0A509AC44, O97578, P05993, P25792, P53634, P69192, P69193, Q26015, Q5RB02, Q60HG6, Q9TY95, Q9TY96, A0A509APV9, A5YVK8, A8DS38, B2LSD2, D3ZZ07, F4JNL3, O10364, O23791, O35186, O45734, O60911, O65039, O70370, O91466, O97397, P04989, P05994, P06797, P07154, P09648, P12412, P14080, P14518, P20721, P25249, P25250, P25251, P25326

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

543 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	65
Likely pathogenic	14
Uncertain significance	180
Likely benign	190
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075099	NM_001814.6(CTSC):c.-55C>A	Pathogenic
1351279	NM_001814.6(CTSC):c.555dup (p.Thr186fs)	Pathogenic
1352166	NM_001814.6(CTSC):c.783del (p.Phe261fs)	Pathogenic
139654	NM_001814.6(CTSC):c.1056del (p.Phe351_Tyr352insTer)	Pathogenic
1398717	NM_001814.6(CTSC):c.570C>G (p.Tyr190Ter)	Pathogenic
1424145	NM_001814.6(CTSC):c.268C>T (p.Gln90Ter)	Pathogenic
1455525	NM_001814.6(CTSC):c.754C>T (p.Gln252Ter)	Pathogenic
1457970	NC_000011.9:g.(?88045475)(88071056_?)del	Pathogenic
1506173	NC_000011.9:g.(?88040961)(88042398_?)del	Pathogenic
1687330	NM_001814.6(CTSC):c.526A>T (p.Lys176Ter)	Pathogenic
1932647	NM_001814.6(CTSC):c.672dup (p.Gln225fs)	Pathogenic
1993744	NM_001814.6(CTSC):c.889+1G>A	Pathogenic
2137218	NM_001814.6(CTSC):c.757G>A (p.Ala253Thr)	Pathogenic
2137220	NM_001814.6(CTSC):c.319-1G>A	Pathogenic
2152122	NM_001814.6(CTSC):c.401G>A (p.Trp134Ter)	Pathogenic
2160925	NM_001814.6(CTSC):c.189dup (p.Val64fs)	Pathogenic
2167619	NM_001814.6(CTSC):c.566_572del (p.Thr189fs)	Pathogenic
2446400	NM_001814.6(CTSC):c.622_628del (p.His208fs)	Pathogenic
2921412	NM_001814.6(CTSC):c.725del (p.Gly242fs)	Pathogenic
2921800	NM_001814.6(CTSC):c.201C>A (p.Tyr67Ter)	Pathogenic
2921926	NM_001814.6(CTSC):c.606dup (p.Arg203Ter)	Pathogenic
2922681	NM_001814.6(CTSC):c.328G>T (p.Glu110Ter)	Pathogenic
2925487	NM_001814.6(CTSC):c.1286G>A (p.Trp429Ter)	Pathogenic
2925490	NM_001814.6(CTSC):c.555G>A (p.Trp185Ter)	Pathogenic
2925491	NM_001814.6(CTSC):c.436del (p.Ser146fs)	Pathogenic
2925492	NM_001814.6(CTSC):c.415G>A (p.Gly139Arg)	Pathogenic
2926323	NM_001814.6(CTSC):c.415G>T (p.Gly139Ter)	Pathogenic
2933811	NM_001814.6(CTSC):c.509dup (p.Tyr170Ter)	Pathogenic
2935808	NM_001814.6(CTSC):c.1122del (p.Phe374fs)	Pathogenic
2936714	NM_001814.6(CTSC):c.407del (p.Cys136fs)	Pathogenic

SpliceAI

1415 predictions. Top by Δscore:

Variant	Effect	Δscore
11:88312386:A:AC	donor_gain	1.0000
11:88312387:C:CC	donor_gain	1.0000
11:88312387:CTTTT:C	donor_gain	1.0000
11:88312391:T:A	donor_gain	1.0000
11:88312550:TTATA:T	acceptor_gain	1.0000
11:88312551:TATA:T	acceptor_gain	1.0000
11:88312553:TA:T	acceptor_gain	1.0000
11:88312555:C:CC	acceptor_gain	1.0000
11:88334932:CTAA:C	donor_loss	1.0000
11:88334933:TAA:T	donor_loss	1.0000
11:88334934:AACCT:A	donor_loss	1.0000
11:88334935:A:C	donor_loss	1.0000
11:88334936:CCTTA:C	donor_loss	1.0000
11:88334952:C:CT	donor_gain	1.0000
11:88334979:AAAG:A	donor_gain	1.0000
11:88335078:TGGTC:T	acceptor_gain	1.0000
11:88335079:GGTC:G	acceptor_gain	1.0000
11:88335080:GTC:G	acceptor_gain	1.0000
11:88335081:TC:T	acceptor_gain	1.0000
11:88335082:CC:C	acceptor_gain	1.0000
11:88335083:C:A	acceptor_loss	1.0000
11:88335083:C:CC	acceptor_gain	1.0000
11:88335083:C:T	acceptor_gain	1.0000
11:88337499:AC:A	donor_gain	1.0000
11:88337500:CC:C	donor_gain	1.0000
11:88294505:CAGC:C	acceptor_gain	0.9900
11:88294508:CCTGA:C	acceptor_loss	0.9900
11:88294509:C:A	acceptor_loss	0.9900
11:88294509:C:CC	acceptor_gain	0.9900
11:88312552:ATA:A	acceptor_gain	0.9900

AlphaMissense

3055 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:88296170:G:C	S284R	0.997
11:88296170:G:T	S284R	0.997
11:88296172:T:G	S284R	0.997
11:88294114:G:C	S428R	0.993
11:88294114:G:T	S428R	0.993
11:88294116:T:G	S428R	0.993
11:88294117:G:C	N427K	0.993
11:88294117:G:T	N427K	0.993
11:88296251:G:C	S257R	0.993
11:88296251:G:T	S257R	0.993
11:88296253:T:G	S257R	0.993
11:88337556:C:A	W39C	0.992
11:88337556:C:G	W39C	0.992
11:88294131:A:G	W423R	0.991
11:88294131:A:T	W423R	0.991
11:88296249:C:T	C258Y	0.991
11:88337558:A:G	W39R	0.990
11:88337558:A:T	W39R	0.990
11:88294185:G:C	H405D	0.989
11:88300578:A:G	W237R	0.989
11:88300578:A:T	W237R	0.989
11:88294111:C:A	W429C	0.988
11:88294111:C:G	W429C	0.988
11:88294184:T:G	H405P	0.988
11:88309251:A:G	W185R	0.988
11:88309251:A:T	W185R	0.988
11:88294113:A:G	W429R	0.986
11:88294113:A:T	W429R	0.986
11:88294175:A:G	L408P	0.986
11:88296146:G:C	S292R	0.986

dbSNP variants (sampled 300 via entrez): RS1000131899 (11:88318302 T>C), RS1000174430 (11:88296056 C>A,G), RS1000262339 (11:88324194 C>G), RS1000373907 (11:88295838 C>A,T), RS1000376485 (11:88325306 C>A,T), RS1000380837 (11:88307936 C>T), RS1000429215 (11:88336607 T>G), RS1000471048 (11:88325751 T>C), RS1000552478 (11:88302041 A>C), RS1000778394 (11:88307931 A>G,T), RS1000778899 (11:88336327 T>G), RS1000825086 (11:88312748 A>C), RS1000850686 (11:88296083 C>G,T), RS1000853550 (11:88320028 C>G,T), RS1000949270 (11:88300914 ATTT>A,ATT)

Disease associations

OMIM: gene MIM:602365 | disease phenotypes: MIM:245000, MIM:245010, MIM:170650

GenCC curated gene-disease

Disease	Classification	Inheritance
Papillon-Lefevre disease	Definitive	Autosomal recessive
Haim-Munk syndrome	Definitive	Autosomal recessive
ectodermal dysplasia syndrome	Strong	Autosomal recessive
periodontitis, aggressive 1	Limited	Unknown

Mondo (6): Papillon-Lefevre disease (MONDO:0009490), Haim-Munk syndrome (MONDO:0009491), periodontitis, aggressive (MONDO:0980757), CTSC-related disorder (MONDO:0800465), ectodermal dysplasia syndrome (MONDO:0019287), periodontitis, aggressive 1 (MONDO:0008226)

Orphanet (2): Haim-Munk syndrome (Orphanet:2342), Papillon-Lefèvre syndrome (Orphanet:678)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000166	Severe periodontitis
HP:0000230	Gingivitis
HP:0000670	Carious teeth
HP:0000704	Periodontitis
HP:0000958	Dry skin
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000998	Hypertrichosis
HP:0001053	Hypopigmented skin patches
HP:0001073	Cigarette-paper scars
HP:0001166	Arachnodactyly
HP:0001231	Abnormal fingernail morphology
HP:0001288	Gait disturbance
HP:0001581	Recurrent skin infections
HP:0001597	Abnormal nail morphology
HP:0001763	Pes planus
HP:0001803	Nail pits
HP:0001805	Onychogryphosis
HP:0001870	Acroosteolysis of distal phalanges (feet)
HP:0002205	Recurrent respiratory infections
HP:0002230	Generalized hirsutism
HP:0002231	Sparse body hair
HP:0002514	Cerebral calcification
HP:0002797	Osteolysis
HP:0002860	Squamous cell carcinoma
HP:0002861	Melanoma
HP:0005406	Recurrent bacterial skin infections
HP:0005830	Flexion contracture of toe

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006585_1476	Blood protein levels	2.000000e-107
GCST008478_35	Neurological blood protein biomarker levels	3.000000e-19
GCST008478_36	Neurological blood protein biomarker levels	3.000000e-25
GCST008478_68	Neurological blood protein biomarker levels	5.000000e-19
GCST90002380_102	Basophil percentage of white cells	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007992	basophil percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D010520	Aggressive Periodontitis	C07.465.714.533.161
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
D010214	Papillon-Lefevre Disease	C16.320.850.475.600; C17.800.428.435.600; C17.800.827.475.600
C537627	Keratosis palmoplantaris with periodontopathia and onychogryposis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2252 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 17,418 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3900409	BRENSOCATIB	3	437

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C1: Papain

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
GSK2793660	Inhibition	9.37	pIC50
brensocatib	Inhibition	8.4	pIC50
IcatCXPZ-01	Inhibition	7.82	pIC50
HSK31858	Inhibition	7.68	pIC50
compound 3d [PMID: 3941405]	Inhibition	5.57	pKi

Binding affinities (BindingDB)

777 measured of 918 human assays (918 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[3-(1-methylazetidin-3-yl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.18 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-2-oxospiro[1H-indole-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.2 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(2-oxospiro[1H-indole-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.3 nM	US-9540373: Substituted spirocycles
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[1’-(oxetan-3-yl)-1-oxospiro[2-benzofuran-3,4’-piperidine]-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.32 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-methyl-2-oxospiro[indole-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.4 nM	US-9540373: Substituted spirocycles
(6S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide	IC50	0.45 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxospiro[2-benzofuran-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxospiro[2-benzofuran-3,3’-pyrrolidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-1-oxospiro[2-benzofuran-3,3’-azetidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methylspiro[1,2-dihydroindene-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(2-oxospiro[1H-indole-3,3’-pyrrolidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.5 nM	US-9540373: Substituted spirocycles
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[3-(1-methylazetidin-3-yl)-2-oxo-1,3-benzothiazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.58 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-(2-fluoro-4-spiro[1,2-dihydroindene-3,4’-piperidine]-5-ylphenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-(1,1’-dimethyl-2-oxospiro[indole-3,4’-piperidine]-5-yl)-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-1-oxospiro[2-benzofuran-3,3’-pyrrolidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-(2-fluoro-4-spiro[1H-2-benzofuran-3,4’-piperidine]-5-ylphenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-1-oxospiro[2-benzofuran-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.7 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxospiro[2-benzofuran-3,3’-azetidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.7 nM	US-9540373: Substituted spirocycles
(6S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-oxo-3H-2-benzofuran-5-yl)phenyl]ethyl]-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide	IC50	0.72 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[1’-(oxetan-3-yl)spiro[1H-2-benzofuran-3,3’-azetidine]-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	0.79 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[5-(4-methylpiperazine-1-carbonyl)thiophen-3-yl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.8 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[5-(1-oxo-3H-2-benzofuran-5-yl)thiophen-2-yl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	KI	0.9 nM	US-8871783: Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-[5-(6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carbonyl)thiophen-3-yl]-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.9 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[1-cyano-2-(3-cyano-9-fluoro-6-oxo-10bH-phenanthridin-8-yl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	0.9 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[5-(4-propan-2-ylpiperazine-1-carbonyl)thiophen-3-yl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methylspiro[1H-2-benzofuran-3,4’-piperidine]-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-3-oxospiro[furo[3,4-c]pyridine-1,4’-piperidine]-6-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[1’-(oxetan-3-yl)spiro[1H-2-benzofuran-3,4’-piperidine]-5-yl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.1 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[3-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.2 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[4-fluoro-3-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.3 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-[1-[2-(dimethylamino)ethyl]-6-oxo-3-pyridinyl]-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.3 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[3-(oxetan-3-yl)-2-oxo-1,3-benzothiazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	1.36 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-7-oxospiro[furo[3,4-b]pyridine-5,4’-piperidine]-3-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.4 nM	US-9540373: Substituted spirocycles
(6S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-5-oxa-8-azaspiro[2.6]nonane-6-carboxamide	IC50	1.4 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(2S,6R)-N-[(1S)-1-cyano-2-[2-fluoro-4-[(3R)-3-methyl-1-oxo-3H-2-benzofuran-5-yl]phenyl]ethyl]-6-fluoro-1,4-oxazepane-2-carboxamide	IC50	1.4 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-(1,1’-dimethyl-2-oxospiro[indole-3,3’-piperidine]-5-yl)-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-oxospiro[furo[3,4-c]pyridine-1,4’-piperidine]-6-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.6 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methyl-3-oxospiro[furo[3,4-c]pyridine-1,3’-pyrrolidine]-6-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.6 nM	US-9540373: Substituted spirocycles
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-methyl-4-oxo-2,3-dihydroquinolin-7-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	1.6 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(2R)-2-[[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]methyl]-4-[(2S)-1,4-oxazepan-2-yl]-4-oxobutanenitrile	IC50	1.6 nM	US-20250163036: DIPEPTIDYL PEPTIDASE 1 INHIBITOR POLYMORPH, PREPARATION METHOD AND USE THEREFOR
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-(1,3-dimethylpyrazol-4-yl)-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.7 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(2S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[3-(1-methylpyrazol-4-yl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	IC50	1.7 nM	US-20250101011: PEPTIDYL NITRILE COMPOUND AND USE THEREOF
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[4-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]phenyl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.8 nM	US-8987249: Substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[1’-(oxetan-3-yl)spiro[5H-furo[3,4-b]pyridine-7,4’-piperidine]-2-yl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.8 nM	US-9540373: Substituted spirocycles
(1R,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-[4-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]phenyl]phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	1.8 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-(5-cyanofuran-2-yl)-2-fluorophenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	2 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[4-(1-oxo-3H-2-benzofuran-5-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	2 nM	US-8999975: Substituted N- [1-cyano-2- (phenyl) ethyl] -2-azabicyclo [2.2.1] heptane-3-carboxamide inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1’-methylspiro[3H-furo[3,4-c]pyridine-1,4’-piperidine]-6-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	2 nM	US-9540373: Substituted spirocycles
(1R,3S,4S)-N-[(1S)-1-cyano-2-[5-(1-methyl-2,3-dioxoindol-6-yl)thiophen-2-yl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	KI	2.1 nM	US-8871783: Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides inhibitors of cathepsin C
(1R,3S,4S)-N-[(1S)-1-cyano-2-[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide	IC50	2.1 nM	US-9713606: Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C

ChEMBL bioactivities

2174 potent at pChembl≥5 of 2180 total, top 49 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	IC50	0.2	nM	CHEMBL5764453
9.60	IC50	0.2512	nM	CHEMBL3936580
9.52	IC50	0.3	nM	CHEMBL5897422
9.52	IC50	0.3	nM	CHEMBL1079888
9.40	IC50	0.3981	nM	CHEMBL4561264
9.40	IC50	0.4	nM	CHEMBL5988711
9.30	IC50	0.5	nM	CHEMBL5821570
9.30	IC50	0.5	nM	CHEMBL5993798
9.30	IC50	0.5	nM	CHEMBL6038478
9.30	IC50	0.5	nM	CHEMBL5842574
9.30	IC50	0.5	nM	CHEMBL5873696
9.22	IC50	0.6	nM	CHEMBL3662670
9.22	IC50	0.6	nM	CHEMBL5959899
9.22	IC50	0.6	nM	CHEMBL5842308
9.22	IC50	0.6	nM	CHEMBL5973708
9.22	IC50	0.6	nM	CHEMBL5847896
9.15	IC50	0.7	nM	CHEMBL3662518
9.15	IC50	0.7	nM	CHEMBL5978060
9.15	IC50	0.7	nM	CHEMBL5759659
9.15	IC50	0.7	nM	CHEMBL1081695
9.10	IC50	0.7943	nM	CHEMBL3261927
9.10	IC50	0.7943	nM	CHEMBL3261926
9.10	IC50	0.8	nM	CHEMBL3662669
9.10	IC50	0.8	nM	CHEMBL3667275
9.10	IC50	0.8	nM	CHEMBL3667371
9.10	IC50	0.8	nM	CHEMBL3667372
9.05	Ki	0.9	nM	CHEMBL3657578
9.05	IC50	0.9	nM	CHEMBL3662671
9.05	IC50	0.9	nM	CHEMBL3667276
9.05	IC50	0.9	nM	CHEMBL3667341
9.05	IC50	0.9	nM	CHEMBL1080780
9.00	IC50	1	nM	CHEMBL3261926
9.00	IC50	1	nM	CHEMBL3261920
9.00	IC50	1	nM	CHEMBL3667277
9.00	IC50	1	nM	CHEMBL3667328
9.00	IC50	1	nM	CHEMBL3667373
9.00	IC50	1	nM	CHEMBL3667394
9.00	IC50	1	nM	CHEMBL4525977
9.00	IC50	1	nM	CHEMBL450997
9.00	IC50	1	nM	CHEMBL5269225
9.00	IC50	1	nM	CHEMBL6009899
9.00	IC50	1	nM	CHEMBL5781403
9.00	IC50	1	nM	CHEMBL1081694
8.96	IC50	1.1	nM	CHEMBL5942494
8.92	IC50	1.2	nM	CHEMBL3667274
8.89	IC50	1.3	nM	CHEMBL3667342
8.89	IC50	1.3	nM	CHEMBL3667374
8.89	IC50	1.3	nM	CHEMBL3667387
8.89	IC50	1.3	nM	CHEMBL3667390

PubChem BioAssay actives

455 with measured affinity, of 784 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-amino-N-[(1S)-1-cyano-2-(5-phenylthiophen-2-yl)ethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0003	uM
4-amino-N-[(1S)-1-cyano-2-[4-(1-methyl-2-oxo-3H-indol-6-yl)phenyl]ethyl]oxane-4-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0003	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-methylsulfanylpyrrolidine-2-carboxamide	1511299: Inhibition of recombinant human DPPI using H-Gly-Arg-AFC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence plate reader analysis	ic50	0.0004	uM
2,5-dibromo-N-[(3R)-1-cyanopyrrolidin-3-yl]benzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0004	uM
(2S)-2-amino-N-[(1S)-2-(1,3-benzothiazol-2-yl)-1-cyanoethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0007	uM
4-amino-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]oxane-4-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0008	uM
4-amino-N-[(1S)-1-cyano-2-[4-(3-methylsulfonylphenyl)phenyl]ethyl]oxane-4-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0008	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-phenylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0009	uM
2-amino-N-[(2S)-4-diazo-1-(4-iodophenyl)-3-oxobutan-2-yl]acetamide	1932757: Inhibition of human Cathepsin C using Ala-4-[ 125 I]Phe-DMK as substrate preincubated for 30 mins followed by substrate addition measured after 6 to 24 hrs	ic50	0.0010	uM
N-[5-[[6-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyanilino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0010	uM
N-[(E,3S)-6-(2,3-dihydroindol-1-yl)-6-oxohex-4-en-3-yl]-4-methyloxane-4-carboxamide	1932761: Inhibition of Cathepsin C (unknown origin)	ic50	0.0010	uM
(2S)-N-[(1S)-1-cyano-2-[4-(4-cyano-3-methylsulfanylphenyl)phenyl]ethyl]piperidine-2-carboxamide	1138553: Inhibition of cathepsin C in human THP1 cells assessed as inhibition of H-Gly-Phe-AFC cleavage by fluorescence assay	ic50	0.0010	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-naphthalen-2-ylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0010	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-fluoropyrrolidine-2-carboxamide	1511299: Inhibition of recombinant human DPPI using H-Gly-Arg-AFC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence plate reader analysis	ic50	0.0016	uM
(2S,4R)-N-[(1S)-1-cyano-2-phenylethyl]-4-methylsulfanyl-4-phenylpyrrolidine-2-carboxamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0017	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-(trifluoromethyl)phenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0018	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0019	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-(4-phenylphenyl)ethyl]butanamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0020	uM
2,5-dibromo-N-[(3R,5S)-1-cyano-5-methylpyrrolidin-3-yl]benzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0020	uM
4-amino-N-[(1S)-1-cyano-2-(4-phenylphenyl)ethyl]oxane-4-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0020	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320489: Reversible inhibition of human recombinant DPP1 by surface plasmon resonance direct binding assay	kd	0.0025	uM
1-amino-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]cyclohexane-1-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0025	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzothiazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0025	uM
N-[2-methyl-5-[[6-[4-(4-methylpiperazin-1-yl)anilino]-3-piperidin-1-yl-2-pyridinyl]oxy]phenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0027	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-(4-methylpiperazin-1-yl)-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0028	uM
(2S)-2-amino-N-[(1S)-1-cyano-2,2-diphenylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0038	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-morpholin-4-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0039	uM
N-[5-[[6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-3-pyrrolidin-1-yl-2-pyridinyl]oxy]-2-(trifluoromethyl)phenyl]prop-2-enamide	1599510: Inhibition of CatL-activated recombinant human C-terminal His10-tagged cathepsin C (25 to 463 residues) expressed in mouse myeloma cells using Gly-Phe-AFC as substrate preincubated for 3 hrs followed by substrate addition and measured after 60 mins	ic50	0.0040	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(2-methyl-1-oxo-3H-isoindol-5-yl)phenyl]ethyl]-4-hydroxypiperidine-2-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0040	uM
(2S,3aS,7aS)-N-[(1S)-1-cyano-2-[4-(3-methylsulfonylphenyl)phenyl]ethyl]-2,3,3a,4,5,6,7,7a-octahydro-1H-indole-2-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0046	uM
N-[5-[[3-(3-hydroxypiperidin-1-yl)-6-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0049	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3-ethyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0050	uM
4-amino-N-[(1S)-1-cyano-2-[4-(2-methyl-3-oxo-1H-isoindol-5-yl)phenyl]ethyl]oxane-4-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0050	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-hydroxypiperidine-2-carboxamide	1138552: Inhibition of recombinant human cathepsin C using H-Gly-Arg-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	ic50	0.0050	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-cyclohexylethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0051	uM
(2S)-2-amino-N-[(1S)-1-cyano-2-(1H-indol-3-yl)ethyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0058	uM
(2S)-N-[(1S)-1-cyano-2-[4-[3-(2,2-difluoroethyl)-2-oxo-1,3-benzoxazol-5-yl]phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320453: Inhibition of human recombinant DPP1 using Gly-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorometric assay	ic50	0.0063	uM
(2S,4S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-4-hydroxypyrrolidine-2-carboxamide	1511299: Inhibition of recombinant human DPPI using H-Gly-Arg-AFC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence plate reader analysis	ic50	0.0063	uM
N-[5-[[6-[[2-methoxy-6-(4-methylpiperazin-1-yl)-3-pyridinyl]amino]-3-piperidin-1-yl-2-pyridinyl]oxy]-2-methylphenyl]prop-2-enamide	1599516: Inhibition of cathepsin C in human THP1 cells using H-Gly-Phe-AFC as substrate preincubated for 4 hrs followed by substrate addition and measured after 60 mins	ic50	0.0065	uM
(2S,3aS,7aS)-N-[(1S)-1-cyano-2-[4-(3-cyano-4-methylsulfonylphenyl)phenyl]ethyl]-2,3,3a,4,5,6,7,7a-octahydro-1H-indole-2-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0065	uM
(2S)-N-[(1S)-1-cyano-2-[4-(3,7-dimethyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-1,4-oxazepane-2-carboxamide	1320454: Inhibition of DPP1 in human U937 cells using Gly-Phe-AFC as substrate preincubated for 60 mins followed by substrate addition by fluorescence assay	ic50	0.0079	uM
3-bromo-N-[(3R)-1-cyanopyrrolidin-3-yl]benzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0079	uM
(2S)-N-[(1S)-1-cyano-2-[4-(2-methyl-1-oxo-3H-isoindol-5-yl)phenyl]ethyl]piperidine-2-carboxamide	1138553: Inhibition of cathepsin C in human THP1 cells assessed as inhibition of H-Gly-Phe-AFC cleavage by fluorescence assay	ic50	0.0079	uM
(2S,4R)-N-[(1S)-1-cyano-2-phenylethyl]-4-fluoro-4-phenylpyrrolidine-2-carboxamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0082	uM
(2S,3aS,6aS)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrole-2-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0093	uM
(2S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]piperidine-2-carboxamide	1138553: Inhibition of cathepsin C in human THP1 cells assessed as inhibition of H-Gly-Phe-AFC cleavage by fluorescence assay	ic50	0.0100	uM
N-[(3R)-1-cyanopyrrolidin-3-yl]-2,5-dimethoxybenzenesulfonamide	570622: Inhibition of human recombinant cathepsin C after 1 hr	ic50	0.0100	uM
(3S)-N-[(1S)-1-cyano-2-[4-(4-cyanophenyl)phenyl]ethyl]-2-azaspiro[4.4]nonane-3-carboxamide	1754932: Inhibition of human cathepsin C	ic50	0.0102	uM
(2S)-2-amino-N-[(1S)-1-cyano-3-phenylpropyl]-3-thiophen-2-ylpropanamide	470223: Inhibition of human recombinant cathepsin C	ic50	0.0110	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148176: Binding affinity to human CTSC incubated for 45 mins by Kinobead based pull down assay	kd	0.0113	uM

CTD chemical–gene interactions

84 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression, affects expression	6
sodium arsenite	increases abundance, increases expression, decreases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
nickel sulfate	decreases expression	4
Tetrachlorodibenzodioxin	decreases expression, increases expression	4
bisphenol A	affects expression, increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
Cadmium Chloride	decreases expression, increases expression	3
cobaltous chloride	decreases expression	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, decreases methylation	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases abundance, increases expression	1
sulindac sulfide	decreases expression	1
toosendanin	decreases expression, decreases reaction, increases phosphorylation, increases reaction	1
ciglitazone	affects binding, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
pentabromodiphenyl ether	decreases expression	1
adefovir dipivoxil	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
lipopolysaccharide, E coli O55-B5	decreases expression	1

ChEMBL screening assays

107 unique, capped per target: 106 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004868	Binding	Inhibition of human recombinant cathepsin C after 10 mins	Inhibition of the activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing. — J Biol Chem
CHEMBL4041066	ADMET	Inhibition of Cathepsin C (unknown origin) at 10 uM	Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer’s Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1PL	Abcam HeLa CTSC KO	Cancer cell line	Female
CVCL_D8JL	Ubigene HCT 116 CTSC KO	Cancer cell line	Male

Clinical trials (associated diseases)

18 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01116934	Not specified	COMPLETED	Cytokines in Papillon-Lefèvre Syndrome
NCT01459302	Not specified	WITHDRAWN	Genetic Study of Familial and Sporadic ALS/Motor Neuron Disease, Miyoshi Myopathy and Other Neuromuscular Disorders
NCT05271435	Not specified	ACTIVE_NOT_RECRUITING	Digital Tools for Assessment of Motor Functions and Falls in ALS
NCT05966038	Not specified	RECRUITING	ALS/MND Natural History Study Data Repository
NCT06408727	Not specified	TEMPORARILY_NOT_AVAILABLE	Intermediate Expanded Access Protocol CNMAu8.EAP04
NCT00001211	Not specified	COMPLETED	Clinical Study of Oral Endosseous Titanium Implants in Edentulous Subjects
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States
NCT01108770	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia
NCT02896387	Not specified	TERMINATED	Ability of a Molecule (Prima) to Restore Physiological Differentiation in Epithelium Expressing Gene p63
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07468019	Not specified	RECRUITING	Organization’s Unique Protocol ID
NCT03340012	Not specified	UNKNOWN	Clinical and Radiographic Evaluation of Guided Tissue Regeneration With Radiation-sterilized Allogenic Bone Grafts or Xenogenic Grafts for the Treatment of Intrabony Defects in Aggressive Periodontitis
NCT04264624	Not specified	COMPLETED	Efficacy of Sub-gingival Air-polishing With Erythritol in the Treatment of Periodontitis
NCT05108727	Not specified	COMPLETED	Diode Laser With Periodontal Flap Surgery in Periodontitis
NCT05112471	Not specified	COMPLETED	Efficacy of GBT vs SRP+US, in the Treatment of Severe Generalized Periodontitis.
NCT07526883	Not specified	COMPLETED	The Effect of Non-Surgical Periodontal Treatment on Systemic Inflammatory Markers and Lipid Profile in Young Adults With Severe Periodontitis