CTSS

Summary

CTSS (cathepsin S, HGNC:2545) is a protein-coding gene on chromosome 1q21.3, encoding Cathepsin S (P25774). Thiol protease.

The preproprotein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that participates in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The mature protein cleaves the invariant chain of MHC class II molecules in endolysosomal compartments and enables the formation of antigen-MHC class II complexes and the proper display of extracellular antigenic peptides by MHC-II. The mature protein also functions as an elastase over a broad pH range. When secreted from cells, this protein can remodel components of the extracellular matrix such as elastin, collagen, and fibronectin. This gene is implicated in the pathology of many inflammatory and autoimmune diseases and, given its elastase activity, plays a significant role in some pulmonary diseases. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 1520 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 28 total
• Druggable target: yes — 12 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004079

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2545
Approved symbol	CTSS
Name	cathepsin S
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163131
Ensembl biotype	protein_coding
OMIM	116845
Entrez	1520

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 13 protein_coding, 6 nonsense_mediated_decay, 4 retained_intron

ENST00000368985, ENST00000448301, ENST00000472977, ENST00000480760, ENST00000483930, ENST00000607427, ENST00000679512, ENST00000679582, ENST00000679898, ENST00000680288, ENST00000680311, ENST00000680466, ENST00000680471, ENST00000680664, ENST00000680931, ENST00000681357, ENST00000681444, ENST00000681728, ENST00000681863, ENST00000857595, ENST00000857596, ENST00000962999, ENST00000963000

RefSeq mRNA: 2 — MANE Select: NM_004079 NM_001199739, NM_004079

CCDS: CCDS55634, CCDS968

Canonical transcript exons

ENST00000368985 — 8 exons

Exon	Start	End
ENSE00001448523	150764638	150764764
ENSE00001874248	150730188	150733145
ENSE00001922877	150765698	150765778
ENSE00003459282	150757858	150757980
ENSE00003464542	150751781	150752008
ENSE00003525779	150755001	150755150
ENSE00003698961	150750006	150750171
ENSE00003699493	150747777	150747879

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 99.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 160.5591 / max 5514.8933, expressed in 1057 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14353	123.9158	897
14354	35.6134	879
14350	0.8576	223
14345	0.0898	39
14346	0.0826	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.94	gold quality
mononuclear cell	CL:0000842	99.93	gold quality
leukocyte	CL:0000738	99.92	gold quality
granulocyte	CL:0000094	99.66	gold quality
blood	UBERON:0000178	99.40	gold quality
rectum	UBERON:0001052	99.28	gold quality
bone marrow cell	CL:0002092	99.14	gold quality
gall bladder	UBERON:0002110	98.60	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.55	gold quality
colonic mucosa	UBERON:0000317	98.45	gold quality
vermiform appendix	UBERON:0001154	98.43	gold quality
bone marrow	UBERON:0002371	98.34	gold quality
colonic epithelium	UBERON:0000397	98.25	gold quality
trabecular bone tissue	UBERON:0002483	98.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.04	gold quality
bronchial epithelial cell	CL:0002328	97.94	gold quality
mucosa of transverse colon	UBERON:0004991	97.88	gold quality
spleen	UBERON:0002106	97.87	gold quality
right lung	UBERON:0002167	97.64	gold quality
lymph node	UBERON:0000029	97.09	gold quality
epithelium of bronchus	UBERON:0002031	96.89	gold quality
upper lobe of left lung	UBERON:0008952	96.83	gold quality
epithelium of nasopharynx	UBERON:0001951	96.73	gold quality
upper lobe of lung	UBERON:0008948	96.66	gold quality
ileal mucosa	UBERON:0000331	96.41	gold quality
bronchus	UBERON:0002185	96.37	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.24	gold quality
palpebral conjunctiva	UBERON:0001812	96.10	gold quality
tonsil	UBERON:0002372	95.98	gold quality
lower lobe of lung	UBERON:0008949	95.97	gold quality

Single-cell (SCXA)

Detected in 37 experiment(s), a significant marker in 36.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	7318.71
E-GEOD-150728	yes	5484.29
E-GEOD-130148	yes	4533.69
E-MTAB-9221	yes	3576.48
E-GEOD-149689	yes	3386.94
E-MTAB-10432	yes	2877.22
E-MTAB-8498	yes	2678.91
E-MTAB-8207	yes	2555.86
E-HCAD-4	yes	2485.78
E-CURD-126	yes	2311.73
E-CURD-112	yes	2238.45
E-MTAB-6701	yes	2218.07
E-HCAD-32	yes	2125.78
E-HCAD-15	yes	2114.85
E-MTAB-10553	yes	2002.71

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF1, IRF2, NGF, PPARG, SPI1

miRNA regulators (miRDB)

108 targeting CTSS, 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-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929

Literature-anchored findings (GeneRIF, showing 40)

• Cathepsin S activity is detectable in human keratinocytes and is selectively upregulated upon stimulation with interferon-gamma. (PMID:12164923)
• the subcellular distribution of cathepsin B, L, and S activities underwent a shift from endosome to lysosome localization during monocyte differentiation in cell culture (PMID:12437117)
• an additional sorting motif in procathepsin S besides the classical Man-6-P recognition signal (PMID:12643447)
• Cathepsin S activity is required for efficient surface display of MHC class II in myoblasts from patients with inflammatory myopathies and on myoblasts stimulated by IFN-gamma. (PMID:12742663)
• cathepsin S efficiently degrades MHC class II-associated invariant chain in nonprofessional antigen-presenting cells (PMID:12748383)
• Data show that CatS expression is up-regulated in astrocytoma cells and provide evidence for a potential role for CatS in invasion. (PMID:12819022)
• in contrast with results from dendritic cells, inhibition of CatS activity prevented N-terminal processing of invariant chain Ii but did not alter the subcellular trafficking or surface delivery of class II complexes (PMID:14966190)
• Cathepsin S may have a significant influence on human atherogenesis. (PMID:16140306)
• The presence of active cathepsins L, K and S suggests that they contribute to the extracellular breakdown of the extracellular matrix. (PMID:16354158)
• The decrease in CTSS concentrations in the circulation may contribute to vascular improvement in obese subjects after weight loss. (PMID:16394095)
• plays an important role in atherosclerotic plaque destabilization and rupture (PMID:16410454)
• cathepsin S may serve as a useful prognostic indicator and potential target for anti-invasive therapy (PMID:16550604)
• CTSS released locally by preadipocytes promotes adipogenesis, suggesting a possible contribution of this protease to fat mass expansion in obesity (PMID:16825321)
• non-fat cells in human adipose tissue contribute to most of the release of cathepsin S seen during primary culture of adipose tissue explants from obese women (PMID:16839849)
• Crystal structure of the active-site mutant Cys25 –> Ala of glycosylated human procathepsin S. (PMID:17075137)
• analysis of human cathepsins K, L, and S iunteractions with elastins (PMID:17227755)
• secretory leukocyte protease inhibitor can inhibit interferon-gamma-induced cathepsin S production by macrophages (PMID:17878156)
• Four novel functional polymorphisms were identified in the cathepsin S gene, in the 5–flaning region, which has a possible association with pulmonary emphysema in Japanese patients. (PMID:18410260)
• evidence that CTSS sequence variations are associated with two human metabolic risk factors for cardiovascular diseases: plasma Apo-A1 and HDL-C concentrations. (PMID:18565099)
• analysis of cathepsin S activity in antigen presenting cells using a novel specific substrate (PMID:18957408)
• radiation induced CatS expression via ROS-IFN-gamma pathways, and this increased expression may be involved in radioresistance (PMID:19101991)
• CIITA transfection did not induce cathepsin S, an important protease responsible for the degradation of the invariant chain, and thus for binding of the peptides to the MHC class II binding groove (PMID:19104823)
• In contrast to cathepsin S, cathepsin H values did not correlate with markers of inflammation, indicating a specific role for cathepsin H in the pleural host response. (PMID:19404922)
• A significantly higher number of cathepsin S expressing macrophages was found in castration-resistant than in hormone naive high grade tumours in patients. (PMID:19487544)
• cathepsin S is necessary for invariant chain proteolysis in T cells; CD4(+)HLA-DR(+) T cells down-regulated cathepsin S expression (PMID:19553543)
• The researchers found no evidence of an association between the CTSS -25G/A polymorphism and the presence of coronary artery disease in a Chinese population. (PMID:19593952)
• U87 tumour cells significantly enhance the proliferation of co-cultured endothelial cells by a mechanism involving cathepsin B, but not cathepsin S (PMID:19700239)
• Our data provide first evidence that Cathepsin S expression is selectively induced in psoriatic keratinocytes. (PMID:19849712)
• Results describe a sensitive and selective cathepsin S substrate that permits continuous measurement of the enzymatic activity even in crude tissue extracts. (PMID:20045715)
• In humans, cathepsin S is more influenced than cathepsins L and K by changes in energy balance in adipose tissue and circulation (PMID:20164293)
• cathepsin S was found to be significantly elevated in rheumatoid arthritis and osteoarthritis synovial fluid. (PMID:20180636)
• the immunosuppressive effects of IL-10-STAT3 on MHC-II antigen presentation may occur via the inhibition of cathepsin S expres (PMID:20356901)
• Data show that plasma levels of cathepsin S mRNA, but not cathepsin B mRNA, are increased in patients with coronary atherosclerosis. (PMID:20880494)
• These data indicate that cathepsins B, L and S may act as cell-death mediators in in monocytic cells infected with ICP4 and Us3 deletion mutant herpes simplex virus type 1. (PMID:20881085)
• Down-regulation of cathepsin S was found in inverted papilloma tissues as compared with its expression level in normal sinus mucosa tissues. (PMID:21038029)
• Cathepsin S activity in human whole blood was dependent on the time of blood collection, suggesting that cathepsin S activity is subject to circadian variations. (PMID:21094118)
• We investigated the modulation of Cathepsin S, Cathepsin B and Cystatin C expression in immune cells by interferon (IFN)-beta, and their role in cell migration (PMID:21112096)
• results suggest that cathepsin S and cystatin C may contribute to disease activity in multiple sclerosis, specifically in a subgroup of patients that are responsive to IFN-beta therapy (PMID:21143385)
• results suggest that CTSS mediated atherogenesis may be associated with a CD40 mediated inflammatory and immune response. Further invasive atheroma analysis is reasonable (PMID:21223957)
• Serum cathepsin S showed significantly lower values 4 days after surgery (PMID:21250859)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctss2.2	ENSDARG00000013771
danio_rerio	ctss2.1	ENSDARG00000074656
mus_musculus	Ctss	ENSMUSG00000038642
rattus_norvegicus	Ctss	ENSRNOG00000021157
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), CTSC (ENSG00000109861), CTSL (ENSG00000135047), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Protein

Protein identifiers

Cathepsin S — P25774 (reviewed: P25774)

All UniProt accessions (12): A0A7P0T7Z6, A0A7P0T844, A0A7P0T8A1, A0A7P0T8H4, P25774, A0A7P0T8U1, A0A7P0T904, A0A7P0TAQ0, A0A7P0TB77, A0A804DAZ0, U3KPS4, U3KQE7

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules and MHC class II antigen presentation. The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L. Elicits itch by mediating cleavage and activation of MRGPRX1.

Subunit / interactions. Monomer.

Subcellular location. Lysosome. Secreted. Cytoplasmic vesicle. Phagosome.

Similarity. Belongs to the peptidase C1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P25774-1	1	yes
P25774-2	2

RefSeq proteins (2): NP_001186668, NP_004070* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000169	Pept_cys_AS	Active_site
IPR000668	Peptidase_C1A_C	Domain
IPR013128	Peptidase_C1A	Family
IPR013201	Prot_inhib_I29	Domain
IPR025660	Pept_his_AS	Active_site
IPR025661	Pept_asp_AS	Active_site
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR039417	Peptidase_C1A_papain-like	Domain

Pfam: PF00112, PF08246

Enzyme classification (BRENDA):

• EC 3.4.22.27 — cathepsin S (BRENDA: 16 organisms, 211 substrates, 1033 inhibitors, 84 Km, 41 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-VAL-VAL-ARG-7-AMIDO-4-METHYLCO	0.006–0.288	10
BENZYLOXYCARBONYL-LEU-ARG-7-AMIDO-4-METHYLCOUMAR	0.0171–0.0534	6
BENZYLOXYCARBONYL-PHE-ARG-7-AMIDO-4-METHYLCOUMAR	0.0147–0.042	5
BENZYLOXYCARBONYL-PHE-VAL-ARG-7-AMIDO-4-METHYLCO	0.0121–0.0125	2
(4-METHYL-7-[[(2S)-2-(4-[(1S)-1-(4-METHYLCYCLOHE	0.017	1
(7-METHOXYCOUMARIN-4-YL)-ACETYL-GRWPPMGLPWEK(2,4	0.0056	1
(7-[[(2S)-2-(4-[(1S)-1,2-DIMETHYL-1-[(PHENYLCARB	0.41	1
(7-[[(2S)-2-(4-[(1S)-1,2-DIMETHYL-1-[(THIOPHEN-3	0.3	1
(7-[[(2S)-2-(4-[(1S)-1-CYCLOHEXYL-1-[(PHENYLCARB	0.057	1
(7-[[(2S)-2-(4-[(1S)-1-CYCLOHEXYL-1-[(THIOPHEN-3	0.13	1
BENZOYL-PHE-VAL-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0081	1
BENZYLOXYCARBONYL-LEU-LEU-ARG-7-AMIDO-4-METHYLCO	0.0034	1
GRWH-NORLEUCINE-VGLRWE-LYS(2,4-DINITROPHENYL)-D-	0.0016	1
GRWHDVGLRWE-LYS(2,4-DINITROPHENYL)-D-ARG-NH2	0.0019	1
GRWHFVGLRWE-LYS(2,4-DINITROPHENYL)-D-ARG-NH2	0.0014	1

UniProt features (47 total): helix 16, strand 12, disulfide bond 4, active site 3, turn 3, sequence variant 2, signal peptide 1, propeptide 1, splice variant 1, mutagenesis site 1, sequence conflict 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

62 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9GJ2	X-RAY DIFFRACTION	1.15
6YYR	X-RAY DIFFRACTION	1.3
3OVX	X-RAY DIFFRACTION	1.49
2H7J	X-RAY DIFFRACTION	1.5
6YYO	X-RAY DIFFRACTION	1.5
2HHN	X-RAY DIFFRACTION	1.55
8RND	X-RAY DIFFRACTION	1.56
4P6G	X-RAY DIFFRACTION	1.58
2FRQ	X-RAY DIFFRACTION	1.6
2OP3	X-RAY DIFFRACTION	1.6
3N3G	X-RAY DIFFRACTION	1.6
2FQ9	X-RAY DIFFRACTION	1.65
2FT2	X-RAY DIFFRACTION	1.7
8PI3	X-RAY DIFFRACTION	1.73
5QC8	X-RAY DIFFRACTION	1.74
5QBV	X-RAY DIFFRACTION	1.8
1NQC	X-RAY DIFFRACTION	1.8
2HH5	X-RAY DIFFRACTION	1.8
4P6E	X-RAY DIFFRACTION	1.8
5QCC	X-RAY DIFFRACTION	1.8
1MS6	X-RAY DIFFRACTION	1.9
2F1G	X-RAY DIFFRACTION	1.9
2FRA	X-RAY DIFFRACTION	1.9
2HXZ	X-RAY DIFFRACTION	1.9
3N4C	X-RAY DIFFRACTION	1.9
5QC0	X-RAY DIFFRACTION	1.9
5QC7	X-RAY DIFFRACTION	1.9
2FUD	X-RAY DIFFRACTION	1.95
5QCD	X-RAY DIFFRACTION	1.95
2R9M	X-RAY DIFFRACTION	1.97

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25774-F1	94.51	0.89

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): 139; 278; 298

Disulfide bonds (4): 272–320, 126–224, 136–180, 170–213

Glycosylation sites (1): 104

Mutagenesis-validated functional residues (1):

Position	Phenotype
104	abolishes glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-1236977	Endosomal/Vacuolar pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1679131	Trafficking and processing of endosomal TLR
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-2132295	MHC class II antigen presentation
R-HSA-6798695	Neutrophil degranulation
R-HSA-9766229	Degradation of CDH1
R-HSA-9958810	SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)
R-HSA-1236975	Antigen processing-Cross presentation
R-HSA-1280218	Adaptive Immune System
R-HSA-1474244	Extracellular matrix organization
R-HSA-1474290	Collagen formation
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 444 (showing top): MODULE_172, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_CATION_CHANNEL_ACTIVITY, SWEET_KRAS_ONCOGENIC_SIGNATURE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_SECRETORY_GRANULE, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, MODULE_45, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOZGIT_ESR1_TARGETS_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (16): toll-like receptor signaling pathway (GO:0002224), adaptive immune response (GO:0002250), regulation of antigen processing and presentation (GO:0002577), proteolysis (GO:0006508), immune response (GO:0006955), response to acidic pH (GO:0010447), protein processing (GO:0016485), antigen processing and presentation (GO:0019882), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), extracellular matrix disassembly (GO:0022617), collagen catabolic process (GO:0030574), basement membrane disassembly (GO:0034769), antigen processing and presentation of peptide antigen (GO:0048002), obsolete proteolysis involved in protein catabolic process (GO:0051603), cellular response to thyroid hormone stimulus (GO:0097067), positive regulation of cation channel activity (GO:2001259)

GO Molecular Function (10): fibronectin binding (GO:0001968), cysteine-type endopeptidase activity (GO:0004197), serine-type endopeptidase activity (GO:0004252), collagen binding (GO:0005518), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), laminin binding (GO:0043236), proteoglycan binding (GO:0043394), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), lysosome (GO:0005764), late endosome (GO:0005770), extracellular matrix (GO:0031012), endolysosome lumen (GO:0036021), lysosomal lumen (GO:0043202), phagocytic vesicle (GO:0045335), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Extracellular matrix organization	2
Adaptive Immune System	2
Innate Immune System	2
Immune System	2
Antigen processing-Cross presentation	1
Toll-like Receptor Cascades	1
Collagen formation	1
Regulation of CDH1 Function	1
Activation of STAT3 by cadherin engagement	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
antigen processing and presentation	2
immune system process	2
endopeptidase activity	2
intracellular organelle lumen	2
pattern recognition receptor signaling pathway	1
immune response	1
regulation of immune system process	1
protein metabolic process	1
response to stimulus	1
response to pH	1
proteolysis	1
protein maturation	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
cellular component disassembly	1
extracellular matrix organization	1
catabolic process	1
collagen metabolic process	1
extracellular matrix disassembly	1
basement membrane organization	1
cellular response to hormone stimulus	1
response to thyroid hormone	1
monoatomic cation channel activity	1
positive regulation of ion transmembrane transporter activity	1
positive regulation of cation transmembrane transport	1
cysteine-type peptidase activity	1
serine-type peptidase activity	1
protein-containing complex binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
extracellular matrix binding	1
carbohydrate derivative binding	1
binding	1
catalytic activity	1
cellular anatomical structure	1
lytic vacuole	1
endosome	1
external encapsulating structure	1

Protein interactions and networks

STRING

4671 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSS	MPO	P05164	963
CTSS	CST3	P01034	943
CTSS	CSTA	P01040	906
CTSS	CSTB	P04080	895
CTSS	CTSD	P07339	883
CTSS	CST4	P01036	881
CTSS	LGMN	Q99538	877
CTSS	ELANE	P08246	875
CTSS	CTSA	P10619	769
CTSS	MMP9	P14780	769
CTSS	ACE2	Q9BYF1	767
CTSS	CD74	P04233	764
CTSS	TIMP1	P01033	748
CTSS	CST6	Q15828	743
CTSS	TMPRSS2	O15393	736

IntAct

5 interactions, top by confidence:

A	B	Type	Score
IRF2	CTSS	psi-mi:“MI:0914”(association)	0.530
CTSS	tktA	psi-mi:“MI:0915”(physical association)	0.000
	CTSS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (221): CTSS (Affinity Capture-MS), BRCA1 (Affinity Capture-Western), CTSS (Two-hybrid), CTSS (Proximity Label-MS), CTSS (Reconstituted Complex), CTSS (Reconstituted Complex), S (Biochemical Activity), S (Biochemical Activity), CTSS (Affinity Capture-MS), CTSS (Affinity Capture-MS), CLGN (Affinity Capture-MS), SEC16A (Affinity Capture-MS), B4GAT1 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), MYO1B (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4F2V5, O35186, O45734, O60911, O65039, O65493, O70370, O97397, P04988, P06797, P07154, P07711, P12412, P13277, P25251, P25326, P25773, P25774, P25782, P25784, P25803, P25975, P43156, P43235, P43236, P54640, P55097, P61276, P61277, Q02765, Q23894, Q24940, Q26636, Q28944, Q3ZKN1, Q5E968, Q5E998, Q63088, Q86GF7, Q8H166

Diamond homologs: A0A068CNX1, A0A072UTP9, A0A0F7G352, A0A1S4F2V5, A2XQE8, A5HII1, B2LSD2, F4JNL3, O35186, O45734, O46427, O60911, O65039, O65493, O70370, O97397, P00785, P00786, P04989, P05167, P06797, P07154, P07711, P09648, P09668, P0DO76, P12412, P13277, P15242, P25251, P25326, P25773, P25774, P25776, P25777, P25778, P25782, P25784, P25803, P25804

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CTSS	“up-regulates quantity”	“peptide antigen”	“chemical modification”
CTSS	“down-regulates quantity”	oligopeptide	“chemical modification”
CTSS	up-regulates	ECM_disassembly
CTSS	“down-regulates quantity by destabilization”	BGLAP	cleavage
TFE3	“up-regulates quantity by expression”	CTSS	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

857 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150750005:CCA:C	donor_gain	1.0000
1:150750010:T:TA	donor_gain	1.0000
1:150750170:TC:T	acceptor_gain	1.0000
1:150750170:TCCTG:T	acceptor_loss	1.0000
1:150750171:CC:C	acceptor_gain	1.0000
1:150750171:CCTG:C	acceptor_loss	1.0000
1:150750172:C:CC	acceptor_gain	1.0000
1:150750172:CTG:C	acceptor_loss	1.0000
1:150751777:GCA:G	donor_loss	1.0000
1:150751778:CA:C	donor_loss	1.0000
1:150751779:A:AC	donor_gain	1.0000
1:150751779:A:C	donor_loss	1.0000
1:150751780:C:CC	donor_gain	1.0000
1:150752007:CC:C	acceptor_gain	1.0000
1:150752008:CC:C	acceptor_gain	1.0000
1:150755146:CTGGT:C	acceptor_gain	1.0000
1:150755151:C:CC	acceptor_gain	1.0000
1:150757853:CCTA:C	donor_loss	1.0000
1:150757855:TA:T	donor_loss	1.0000
1:150757856:A:AC	donor_gain	1.0000
1:150757856:A:AT	donor_loss	1.0000
1:150757857:C:CC	donor_gain	1.0000
1:150757977:CATT:C	acceptor_gain	1.0000
1:150757979:TT:T	acceptor_gain	1.0000
1:150757981:C:CC	acceptor_gain	1.0000
1:150757981:CT:C	acceptor_loss	1.0000
1:150757982:T:C	acceptor_loss	1.0000
1:150757987:CATAA:C	acceptor_gain	1.0000
1:150757988:A:C	acceptor_gain	1.0000
1:150764599:C:CA	donor_gain	1.0000

AlphaMissense

2181 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150747793:A:G	W294R	0.995
1:150747793:A:T	W294R	0.995
1:150751919:A:C	S163R	0.994
1:150751919:A:T	S163R	0.994
1:150751921:T:G	S163R	0.994
1:150751990:A:G	W140R	0.994
1:150751990:A:T	W140R	0.994
1:150757961:C:G	R49P	0.994
1:150747782:T:A	K297N	0.993
1:150747782:T:G	K297N	0.993
1:150751979:A:C	S143R	0.993
1:150751979:A:T	S143R	0.993
1:150751981:T:G	S143R	0.993
1:150751988:C:A	W140C	0.993
1:150751988:C:G	W140C	0.993
1:150757940:A:G	L56P	0.993
1:150757951:C:A	W52C	0.993
1:150757951:C:G	W52C	0.993
1:150733083:C:G	C320S	0.992
1:150733084:A:T	C320S	0.992
1:150747779:G:C	N298K	0.992
1:150747779:G:T	N298K	0.992
1:150747791:C:A	W294C	0.992
1:150747791:C:G	W294C	0.992
1:150733130:A:C	F304L	0.991
1:150733130:A:T	F304L	0.991
1:150733132:A:G	F304L	0.991
1:150751982:G:C	F142L	0.990
1:150751982:G:T	F142L	0.990
1:150751984:A:G	F142L	0.990

dbSNP variants (sampled 300 via entrez): RS1000052625 (1:150738377 G>A), RS1000106333 (1:150730782 A>G,T), RS1000137095 (1:150755195 A>G), RS1000281354 (1:150736083 G>A), RS1000420635 (1:150744911 C>T), RS1000524669 (1:150761075 A>G), RS1000576656 (1:150753298 A>AT), RS1000578388 (1:150761521 C>A,T), RS1000718965 (1:150736760 C>T), RS1000732659 (1:150753179 T>C), RS1000808908 (1:150753727 A>T), RS1000841135 (1:150744576 T>C), RS1000843109 (1:150744706 T>C), RS1000895247 (1:150745014 G>C,T), RS1000922774 (1:150760699 C>T)

Disease associations

OMIM: gene MIM:116845 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001966_1	Rhegmatogenous retinal detachment	1.000000e-07
GCST002226_2	Fat body mass	4.000000e-08
GCST003419_2	Congenital left-sided heart lesions	9.000000e-07
GCST005951_38	Body mass index	4.000000e-09
GCST006585_1647	Blood protein levels	4.000000e-62
GCST010479_51	Coronary artery disease	9.000000e-09
GCST011125_1	Caffeine consumption from coffee	5.000000e-09
GCST011126_1	Caffeine consumption from coffee or tea	1.000000e-23
GCST011126_7	Caffeine consumption from coffee or tea	1.000000e-26
GCST90002389_69	Lymphocyte percentage of white cells	3.000000e-21
GCST90002395_322	Mean platelet volume	4.000000e-13
GCST90011899_72	Aspartate aminotransferase levels	2.000000e-18
GCST90013410_31	Basal cell carcinoma	3.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111368 (SELECTIVITY GROUP), CHEMBL2954 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

12 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 10,905 (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
CHEMBL218394	BOCEPREVIR	4	2,760
CHEMBL231813	TELAPREVIR	4	3,301
CHEMBL4802135	NIRMATRELVIR	4	1,262
CHEMBL501849	SIMEPREVIR	4	1,797
CHEMBL4525964	VANIPREVIR	3	431
CHEMBL481611	ODANACATIB	3	804
CHEMBL203665	RELACATIB	2	115
CHEMBL371064	BALICATIB	2	97
CHEMBL4297638	PETESICATIB	2	45
CHEMBL5095230	ATUZAGINSTAT	2	72
CHEMBL5591580	IBUZATRELVIR	2	20
CHEMBL91704	K-777	2	201

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 (8 total), top 8:

Ligand	Action	Affinity	Parameter
petesicatib	Inhibition	10.0	pIC50
VBY-825	Inhibition	9.89	pKi
compound (R)-26 [PMID: 22686657]	Inhibition	9.3	pKi
compound 4d [PMID: 38746883]	Inhibition	9.15	pIC50
LHVS	Inhibition	9.0	pIC50
K11777	Inhibition	8.7	pKi
LY3000328	Inhibition	8.11	pIC50
odanacatib	Inhibition	7.22	pIC50

Binding affinities (BindingDB)

962 measured of 1243 human assays (1245 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.003 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.003 nM
2-cyano-4-(cyclohexylamino)-N-[2-(3-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	IC50	0.009 nM
2-cyano-4-(cyclohexylamino)-N-(2-phenylethyl)pyrimidine-5-carboxamide	IC50	0.01 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[3-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.011 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.011 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.013 nM
2-cyano-4-(cyclohexylamino)-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	IC50	0.022 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.025 nM
2-cyano-N-[[4-(trifluoromethyl)phenyl]methyl]-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.029 nM	US-8524710: Pyrrolidine derivatives
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{3-[2-(1H-imidazol-1-yl)ethoxy]-4-methoxyphenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.031 nM
2-cyano-4-(cyclohexylamino)-N-{2-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.047 nM
4-[(3S)-3-(2-chloro-4-pyrazol-1-ylphenyl)sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.052 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-chloro-4-(4-cyclopropylpiperazin-1-yl)phenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.056 nM	US-8524710: Pyrrolidine derivatives
N-[2-(4-chlorophenyl)propyl]-2-cyano-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.056 nM	US-8524710: Pyrrolidine derivatives
2-cyano-N-(2,2,2-trifluoroethyl)-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.061 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-(2-chloro-4-imidazol-1-ylphenyl)sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.11 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-chloro-4-(2-methoxyethoxy)phenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.13 nM	US-8524710: Pyrrolidine derivatives
(2S)-2-(1-benzofuran-2-ylformamido)-4-methyl-N-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)azepan-4-yl]pentanamide	KI	0.14 nM
4-[(3S)-3-[4-(4-tert-butylpiperazin-1-yl)-2-chlorophenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.15 nM	US-8524710: Pyrrolidine derivatives
2-cyano-4-[(3S)-3-(2,3-dichlorophenyl)sulfonylpyrrolidin-1-yl]-N-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-5-carboxamide	IC50	0.155 nM	US-8524710: Pyrrolidine derivatives
4-(trifluoromethyl)-6-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-2-carbonitrile	IC50	0.167 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-carbonitrile	IC50	0.205 nM	US-8524710: Pyrrolidine derivatives
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(1-thiomorpholin-4-ylcyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.3 nM	US-8802665: Pyrrolidine derivatives
(2S,4R)-4-(3-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(1-piperidin-1-ylcyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.3 nM	US-8802665: Pyrrolidine derivatives
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[4-(pyrrolidin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.3 nM
N-[[1-(4-chlorophenyl)cyclopropyl]methyl]-2-cyano-4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-5-carboxamide	IC50	0.305 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[2-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]pyrimidine-2-carbonitrile	IC50	0.31 nM	US-8524710: Pyrrolidine derivatives
2-cyano-4-[(3S)-3-(2,3-dichlorophenyl)sulfonylpyrrolidin-1-yl]-N-(2,2,2-trifluoroethyl)pyrimidine-5-carboxamide	IC50	0.32 nM	US-8524710: Pyrrolidine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.322 nM	US-9409882: Pyridine derivatives
4-[(3S)-3-(2-chloro-4-fluorophenyl)sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.335 nM	US-8524710: Pyrrolidine derivatives
4-[(3S)-3-[4-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-chlorophenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.355 nM	US-8524710: Pyrrolidine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.375 nM	US-9409882: Pyridine derivatives
tert-butyl 2-[(2S,4R)-4-(2-chloro-4-fluorophenyl)sulfonyl-2-[(1-cyanocyclopropyl)carbamoyl]pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-2-pyridinyl)azetidine-1-carboxylate	IC50	0.377 nM	US-8822505: Azetidine derivatives
(2S,4R)-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3-fluoro-5-iodo-2-pyridinyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.382 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chloro-4-methoxyphenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.393 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.398 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3-methylpiperidin-1-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.4 nM	US-8802665: Pyrrolidine derivatives
(2S,4R)-4-(2-chloro-4-fluorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(1-piperidin-1-ylcyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.4 nM	US-8802665: Pyrrolidine derivatives
(2S,4R)-N-(1-cyanocyclopropyl)-4-(4-methylphenyl)sulfonyl-1-(1-piperidin-1-ylcyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.4 nM	US-8802665: Pyrrolidine derivatives
(2S,4R)-N-(1-cyanocyclopropyl)-1-(1-piperidin-1-ylcyclopropanecarbonyl)-4-[3-(trifluoromethyl)phenyl]sulfonylpyrrolidine-2-carboxamide	IC50	0.4 nM	US-8802665: Pyrrolidine derivatives
4-[(3S)-3-[2-chloro-4-(4-methylpiperazin-1-yl)phenyl]sulfonylpyrrolidin-1-yl]-6-(trifluoromethyl)pyrimidine-2-carbonitrile	IC50	0.415 nM	US-8524710: Pyrrolidine derivatives
(2S,4R)-1-[1-(5-bromo-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.438 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-(4-bromo-2-chlorophenyl)sulfonyl-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.474 nM	US-9409882: Pyridine derivatives
tert-butyl 2-(5-bromo-3-fluoro-2-pyridinyl)-2-[(2S,4R)-4-(2-chloro-4-fluorophenyl)sulfonyl-2-[(1-cyanocyclopropyl)carbamoyl]pyrrolidine-1-carbonyl]azetidine-1-carboxylate	IC50	0.492 nM	US-8822505: Azetidine derivatives
(2S,4R)-4-(2-chlorophenyl)sulfonyl-1-[1-(5-chloro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.492 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(1-piperidin-1-ylcyclopropanecarbonyl)pyrrolidine-2-carboxamide	IC50	0.5 nM	US-8802665: Pyrrolidine derivatives
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(4-methylpiperidin-1-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.5 nM	US-8802665: Pyrrolidine derivatives
(2S,4R)-1-[1-(azepan-1-yl)cyclopropanecarbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.5 nM	US-8802665: Pyrrolidine derivatives
2-cyano-4-[(3S)-3-(2,3-dichlorophenyl)sulfonylpyrrolidin-1-yl]-N-[1-(4-fluorophenyl)cyclopropyl]pyrimidine-5-carboxamide	IC50	0.5 nM	US-8524710: Pyrrolidine derivatives

ChEMBL bioactivities

2770 potent at pChembl≥5 of 2904 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.80	Ki	0.016	nM	CHEMBL5573840
10.54	IC50	0.029	nM	CHEMBL3651506
10.41	Ki	0.039	nM	CHEMBL5573840
10.28	IC50	0.052	nM	CHEMBL3651502
10.25	IC50	0.056	nM	CHEMBL3651503
10.25	IC50	0.056	nM	CHEMBL3651507
10.21	IC50	0.061	nM	CHEMBL3651508
10.05	Ki	0.09	nM	CHEMBL4777335
10.00	IC50	0.1	nM	CHEMBL2207565
10.00	IC50	0.1	nM	CHEMBL2207564
10.00	IC50	0.1	nM	PETESICATIB
10.00	Kd	0.1	nM	CHEMBL155560
10.00	Kd	0.1	nM	CHEMBL356442
9.96	IC50	0.11	nM	CHEMBL3651509
9.89	Ki	0.13	nM	CHEMBL3342185
9.89	IC50	0.13	nM	CHEMBL3651505
9.89	IC50	0.13	nM	CHEMBL386506
9.82	IC50	0.15	nM	CHEMBL3651499
9.82	Ki	0.15	nM	CHEMBL1651361
9.81	IC50	0.155	nM	CHEMBL3651510
9.80	Ki	0.16	nM	CHEMBL1651355
9.80	Ki	0.16	nM	CHEMBL1651357
9.78	IC50	0.167	nM	CHEMBL3651495
9.77	Ki	0.17	nM	CHEMBL1651356
9.75	Ki	0.176	nM	CHEMBL3342184
9.72	Ki	0.19	nM	CHEMBL1651349
9.70	IC50	0.2	nM	CHEMBL251117
9.70	IC50	0.2	nM	CHEMBL443319
9.70	IC50	0.2	nM	CHEMBL251719
9.70	Ki	0.2	nM	CHEMBL4777740
9.70	Ki	0.2	nM	CHEMBL1651352
9.70	Ki	0.2	nM	CHEMBL1651354
9.69	IC50	0.205	nM	CHEMBL3651493
9.64	IC50	0.23	nM	CHEMBL385632
9.60	Ki	0.25	nM	CHEMBL4761229
9.59	Ki	0.26	nM	CHEMBL177914
9.53	IC50	0.296	nM	CHEMBL3649369
9.52	IC50	0.3	nM	CHEMBL2207562
9.52	IC50	0.3	nM	CHEMBL3093935
9.52	Ki	0.3	nM	CHEMBL3640716
9.52	IC50	0.305	nM	CHEMBL3651511
9.52	IC50	0.3	nM	CHEMBL3701872
9.52	IC50	0.3	nM	CHEMBL3701887
9.52	IC50	0.3	nM	CHEMBL250720
9.52	IC50	0.3	nM	CHEMBL400750
9.52	IC50	0.3	nM	CHEMBL398553
9.52	Kd	0.3	nM	CHEMBL153813
9.52	Kd	0.3	nM	CHEMBL152940
9.52	Kd	0.3	nM	CHEMBL149523
9.51	IC50	0.31	nM	CHEMBL3651473

PubChem BioAssay actives

2472 with measured affinity, of 3394 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
N-[(2S)-3-cyclohexyl-1-oxo-1-[[(2S)-1-oxo-3-phenylmethoxypropan-2-yl]amino]propan-2-yl]morpholine-4-carboxamide	2094804: Inhibition of recombinant Cathepsin S (unknown origin) expressed in Escherichia coli using Z-Val-Val-Arg-AMC as substrate by fluorescence based assay	ki	<0.0001	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]thiophene-2-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0001	uM
N-[(2S)-1-[[(1R)-1-cyano-2-[(2-methylphenyl)methoxy]ethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0001	uM
tert-butyl N-[cyano-[2-(dibenzylamino)-2-oxoethyl]amino]carbamate	1168919: Inhibition of human cathepsin S using Z-Phe-Arg-AMC fluorogenic substrate fluorogenic substrate incubated for 60 mins	ki	0.0001	uM
2-cyano-4-(cyclohexylamino)-N-(2-phenylethyl)pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0001	uM
N-[(2R)-1-[(1-cyanocyclopropyl)amino]-1-oxo-3-(4-pyridin-2-ylpiperazin-1-yl)sulfonylpropan-2-yl]-3,3-dimethylbutanamide	1675896: Inhibition of recombinant human Cathepsin S expressed in baculovirus infected insect cells using Z-VVR-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 10 mins by fluorescence assay	ki	0.0001	uM
N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl)benzamide	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0001	uM
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	370547: Inhibition of human recombinant cathepsin S by fluorescence assay	ki	0.0001	uM
(2S,4R)-N-(1-cyanocyclopropyl)-4-[4-(1-methylpyrazol-4-yl)-2-(trifluoromethyl)phenyl]sulfonyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	2094802: Inhibition of Cathepsin S (unknown origin)	ic50	0.0001	uM
N-[(1S)-1-[1-(cyanomethyl)triazol-4-yl]-1-(4-methylcyclohexyl)ethyl]thiophene-3-carboxamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0001	uM
N-[(1S)-1-[1-[(1R)-1-cyanoethyl]triazol-4-yl]-1-(4-methylcyclohexyl)ethyl]thiophene-3-carboxamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0001	uM
[(2S)-3,3-dimethyl-1-[3-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]butan-2-yl] N-[(3S)-1,2-dioxo-1-(1H-pyrazol-5-ylamino)heptan-3-yl]carbamate	1797900: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2006.10.102: “Acyclic, orally bioavailable ketone-based cathepsin K inhibitors.”	ic50	0.0002	uM
tert-butyl N-[[2-[benzyl(methyl)amino]-2-oxoethyl]-cyanoamino]carbamate	1168919: Inhibition of human cathepsin S using Z-Phe-Arg-AMC fluorogenic substrate fluorogenic substrate incubated for 60 mins	ki	0.0002	uM
2-cyano-4-(cyclohexylamino)-N-[2-(3-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0002	uM
(2R)-N-(1-cyanocyclopropyl)-3-(4-pyridin-2-ylpiperazin-1-yl)sulfonyl-2-[(2-thiophen-2-ylacetyl)amino]propanamide	1675896: Inhibition of recombinant human Cathepsin S expressed in baculovirus infected insect cells using Z-VVR-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 10 mins by fluorescence assay	ki	0.0002	uM
(2R)-3-(3-bromophenyl)sulfonyl-N-(1-cyanocyclopropyl)-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0002	uM
(2R)-N-(1-cyanocyclopropyl)-3-(3,4-dichlorophenyl)sulfonyl-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0002	uM
(2R)-N-(1-cyanocyclopropyl)-3-(3,4-dichlorophenyl)sulfonyl-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0002	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-3-cyclohexyl-1-oxopropan-2-yl]carbamate	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-phenylurea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-benzyl-3-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[[4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl)phenyl]methyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0002	uM
benzyl N-[(2S)-1-[[(2S)-1-(4-hydroxyphenyl)-3-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	255215: Apparent inhibitory constant against human cathepsin S	ki	0.0003	uM
N-[(2S)-1-[[(1R)-1-cyano-2-[(2-methylphenyl)methoxy]ethyl]amino]-4,4-dimethyl-1-oxopentan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0003	uM
N-[(2S)-1-[[(1R)-2-[(2-chlorophenyl)methoxy]-1-cyanoethyl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0003	uM
(2R)-N-(1-cyanocyclopropyl)-2-(pyridin-3-ylamino)-3-(4-pyridin-2-ylpiperazin-1-yl)sulfonylpropanamide	1675896: Inhibition of recombinant human Cathepsin S expressed in baculovirus infected insect cells using Z-VVR-AMC as substrate preincubated for 15 mins followed by substrate addition and measured after 10 mins by fluorescence assay	ki	0.0003	uM
(2R)-N-(1-cyanocyclopropyl)-3-[(2,3-difluorophenyl)methylsulfonyl]-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0003	uM
(2R)-N-(1-cyanocyclopropyl)-3-[(2,3-difluorophenyl)methylsulfonyl]-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0003	uM
(2R)-3-(4-bromophenyl)sulfonyl-N-(1-cyanocyclopropyl)-2-[[(1S)-2,2,2-trifluoro-1-phenylethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0003	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]carbamate	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0003	uM
benzyl (2S)-2-[[(2S)-1-[5-(furan-2-yl)-1,3,4-oxadiazol-2-yl]-1-oxopentan-2-yl]carbamoyl]-4-methylpentanoate	266479: Inhibition of human cathepsin S	ki	0.0003	uM
benzyl N-[(3S)-1-[[(2S)-1-[5-(furan-2-yl)-1,3,4-oxadiazol-2-yl]-1-oxohexan-2-yl]amino]-5-methyl-1,2-dioxohexan-3-yl]carbamate	321240: Inhibition of human recombinant cathepsin S	ki	0.0003	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-[4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl)phenyl]urea	554255: Inhibition of human cathepsin S after 30 mins by spectrophotometric assay	ki	0.0003	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-4-methyl-1-oxopentan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0003	uM
(2S,4R)-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)-1-(cyclohexanecarbonyl)pyrrolidine-2-carboxamide	1058734: Inhibition of human cathepsin-S using Z-Val-Val-Arg-AMC as substrate up to 20 mins by fluorescence assay	ic50	0.0003	uM
N-[(1S)-1-[1-[(1R)-1-cyanopentyl]triazol-4-yl]-1-(4-methylcyclohexyl)ethyl]thiophene-3-carboxamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0003	uM
N-[(2S)-3-(1-methylcyclohexyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]morpholine-4-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0004	uM
N-[(2S)-3-(1-methylcyclohexyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-cycloheptyl-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-1-[[(1R)-2-[(2-chlorophenyl)methoxy]-1-cyanoethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]morpholine-4-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0004	uM
N-[(2S)-1-[[(1R)-1-cyano-2-phenylmethoxyethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]furan-2-carboxamide	51529: Equilibrium dissociation constant determined using fluorescence based competitive binding assay towards Cathepsin S	kd	0.0004	uM
(2R)-N-(1-cyanocyclopropyl)-3-(cyclopropylmethylsulfonyl)-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	717412: Inhibition of cathepsin S using FR-aminoluciferin as substrate preincubated for 15 mins before substrate addition measured after 1 hr by luminescence assay	ic50	0.0004	uM
(2R)-N-(1-cyanocyclopropyl)-3-(2-methylpropylsulfonyl)-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0004	uM
(2R)-N-(1-cyanocyclopropyl)-3-(4-fluorophenyl)sulfonyl-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanamide	1797859: Enzyme Inhibition Assay from Article 10.1016/j.bmcl.2007.06.023: “The identification of potent, selective, and bioavailable cathepsin S inhibitors.”	ic50	0.0004	uM
(1R,2R,4R)-4-(benzenesulfonyl)-N-(1-cyanocyclopropyl)-2-[(2S,6R)-2,6-dimethylmorpholine-4-carbonyl]cyclopentane-1-carboxamide	1058734: Inhibition of human cathepsin-S using Z-Val-Val-Arg-AMC as substrate up to 20 mins by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-(1-methylcyclopentyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-(4-methylcyclohexyl)-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609672: Inhibition of human recombinant cathepsin S using Ac-KQLR-AMC as substrate by fluorescence assay	ic50	0.0005	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	4
Cisplatin	decreases expression, decreases response to substance, increases expression	3
sodium arsenite	affects expression, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	increases abundance, decreases expression, affects expression	2
Doxorubicin	decreases expression, affects response to substance	2
Hydrogen Peroxide	increases expression, decreases reaction	2
Nickel	increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
OTX015	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
potassium perchlorate	increases expression	1
glycolaldehyde	decreases activity	1
asperphenamate	affects binding, decreases activity	1
benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide	increases cleavage, increases reaction	1
potassium chromate(VI)	decreases expression	1
benazol P	affects expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
monomethylarsonous acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
thifluzamide	decreases expression	1
picoxystrobin	decreases expression	1

ChEMBL screening assays

328 unique, capped per target: 313 binding, 9 admet, 5 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4678410	Binding	Selectivity index, ratio of pKi for human cathepsin S to pKi for recombinant human cathepsin K using Z-Leu-Arg-AMC as substrate measured after 20 mins	Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L. — Bioorg Med Chem
CHEMBL4041063	ADMET	Inhibition of human cathepsin S expressed in Escherichia coli using Z-Val-Val-Arg-AMC as substrate by kinetic fluorescence assay	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
CHEMBL5576503	Toxicity	Inhibition of human Cathepsin S	A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19. — 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_B9XE	Abcam THP-1 CTSS KO	Cancer cell line	Male
CVCL_D7N6	Ubigene A-549 CTSS KO	Cancer cell line	Male

Clinical trials (associated diseases)

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