CTSK

Summary

CTSK (cathepsin K, HGNC:2536) is a protein-coding gene on chromosome 1q21.3, encoding Cathepsin K (P43235). Thiol protease involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling.

The protein encoded by this gene is a lysosomal cysteine proteinase involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is predominantly expressed in osteoclasts. However, the encoded protein is also expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature.

Source: NCBI Gene 1513 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pycnodysostosis (Definitive, ClinGen)
• GWAS associations: 11
• Clinical variants (ClinVar): 520 total — 41 pathogenic, 69 likely-pathogenic
• Phenotypes (HPO): 73
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000396

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2536
Approved symbol	CTSK
Name	cathepsin K
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	PKND
Ensembl gene	ENSG00000143387
Ensembl biotype	protein_coding
OMIM	601105
Entrez	1513

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 16 protein_coding, 8 retained_intron, 2 nonsense_mediated_decay

ENST00000271651, ENST00000443913, ENST00000480670, ENST00000676680, ENST00000676716, ENST00000676751, ENST00000676824, ENST00000676966, ENST00000676970, ENST00000677330, ENST00000677611, ENST00000677887, ENST00000678275, ENST00000678337, ENST00000678725, ENST00000679090, ENST00000679148, ENST00000679171, ENST00000679178, ENST00000679260, ENST00000923236, ENST00000962226, ENST00000962227, ENST00000962228, ENST00000962229, ENST00000962230

RefSeq mRNA: 1 — MANE Select: NM_000396 NM_000396

CCDS: CCDS969

Canonical transcript exons

ENST00000271651 — 8 exons

Exon	Start	End
ENSE00000959757	150796208	150796898
ENSE00001044450	150806102	150806224
ENSE00001343333	150808214	150808260
ENSE00001602868	150799168	150799273
ENSE00001610479	150799544	150799709
ENSE00002193797	150804021	150804239
ENSE00003473368	150806686	150806806
ENSE00003571731	150805861	150806016

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 99.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.3314 / max 2894.1182, expressed in 1021 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14358	27.5665	801
14359	16.4412	939
14360	3.3237	684

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	99.92	gold quality
stromal cell of endometrium	CL:0002255	99.45	gold quality
skin of hip	UBERON:0001554	99.45	gold quality
gall bladder	UBERON:0002110	99.38	gold quality
tibia	UBERON:0000979	99.23	gold quality
mucosa of stomach	UBERON:0001199	98.78	gold quality
upper leg skin	UBERON:0004262	98.74	gold quality
endocervix	UBERON:0000458	98.73	gold quality
decidua	UBERON:0002450	98.29	gold quality
skin of leg	UBERON:0001511	98.28	gold quality
ectocervix	UBERON:0012249	98.27	gold quality
upper arm skin	UBERON:0004263	98.01	gold quality
body of uterus	UBERON:0009853	97.86	gold quality
zone of skin	UBERON:0000014	97.78	gold quality
calcaneal tendon	UBERON:0003701	97.64	gold quality
mammalian vulva	UBERON:0000997	97.62	gold quality
skin of abdomen	UBERON:0001416	97.62	gold quality
smooth muscle tissue	UBERON:0001135	97.37	gold quality
myometrium	UBERON:0001296	97.22	gold quality
parietal pleura	UBERON:0002400	97.16	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.11	gold quality
mammary duct	UBERON:0001765	97.09	gold quality
thoracic mammary gland	UBERON:0005200	97.09	gold quality
pleura	UBERON:0000977	96.96	gold quality
tendon of biceps brachii	UBERON:0008188	96.89	gold quality
mammary gland	UBERON:0001911	96.82	gold quality
visceral pleura	UBERON:0002401	96.55	gold quality
synovial joint	UBERON:0002217	96.42	gold quality
urethra	UBERON:0000057	96.31	gold quality
layer of synovial tissue	UBERON:0007616	96.31	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	9536.22
E-CURD-112	yes	3066.12
E-MTAB-8142	yes	2292.89
E-MTAB-8207	yes	1902.69
E-HCAD-13	yes	1882.27
E-MTAB-10137	yes	1740.43
E-MTAB-10290	yes	1594.08
E-HCAD-11	yes	1141.88
E-MTAB-7052	yes	1088.68
E-MTAB-7407	yes	452.84
E-MTAB-6701	yes	122.85
E-MTAB-10287	yes	102.83
E-MTAB-8410	yes	61.99
E-GEOD-135922	yes	19.85
E-HCAD-1	yes	18.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPA, FOS, ID1, IKZF4, IL1B, JDP2, JUN, MITF, NFATC1, RUNX1, SPI1, TFE3, TNF, TP53, TXK

miRNA regulators (miRDB)

59 targeting CTSK, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870

Literature-anchored findings (GeneRIF, showing 40)

• This study demonstrates for the first time a critical role of Cathepsin K in cartilage degradation by synovial fibroblasts (SFs) in rheumatoid arthritis (RA) that is comparable to its well-known activity in osteoclasts. (PMID:11733367)
• cathepsin K binds with chondroitin sulfate for collagenase activity (PMID:12039963)
• Selective inhibition of the collagenolytic activity by altering its S2 subsite specificity (PMID:12081494)
• review discusses the human disease pycnodysostosis caused by cathepsin K deficiency and cathepsin K activity and regulation (PMID:12125807)
• data suggest that extracellular cysteine proteases may participate in the regulation of kinin levels at inflammatory sites, and clearly support that cathepsin K may act as a potent kininase (PMID:12492488)
• cathepsin K may have a role in contributing to the invasive potential of prostate cancer (PMID:12568399)
• In db/db mice, cathepsin k(ctsk) increased, as did Mitf and TFE3, two transcription factors involved in ctsk induction in osteoclasts. Ctsk was increased in other obese models including A(y), fat, and tubby. (PMID:12652657)
• cathepsin K is capable to degrade aggrecan complexes at specific cleavage sites (PMID:12887056)
• cathepsin K has a role in lysosomal collagenolytic activity (PMID:14645229)
• Cathepsin K plays a pivotal role in lung matrix homeostasis under physiological and pathological conditions. (PMID:15161653)
• RANKL-induced cathepsin K gene expression is cooperatively regulated by the combination of the transcription factors and p38 MAP kinase in a gradual manner. (PMID:15304486)
• These findings suggest that a specific function of human cathepsin X is unlikely to result from sequence specificity, but rather from a combination of its unique positional specificity and the co-localization of enzyme and substrate. (PMID:15737607)
• heparan sulfate proteoglycans can regulate the cellular trafficking and the enzymatic activity of cathepsin X (PMID:15797245)
• results support the role of cathepsin K as a major proteinase in osteoclastic bone resorption (PMID:15826870)
• Several novel ketoamide-based inhibitors of cathepsin K have been identified. (PMID:15837295)
• Cathepsin X is not involved in degradation of extracellular matrix, a proteolytic event leading to tumor cell invasion and metastasis, and its expression, restricted to immune cells suggests a role in phagocytosis and the regulation of immune response. (PMID:15878337)
• Cathepsin K co-localized with TRAP in osteoclast-resorptive compartments, supporting a role for cathepsin K in the extracellular processing of monomeric TRAP in the resorption lacuna. (PMID:15929988)
• Osteoblastic cathepsin K may thus contribute to collagenous matrix maintenance and recycling of improperly processed collagen I (PMID:16337236)
• The presence of active cathepsins L, K and S suggests that they contribute to the extracellular breakdown of the extracellular matrix. (PMID:16354158)
• Active cathepsin X mediates the function of beta(2) integrin receptors during cell adhesion and that it could also be involved in other processes associated with beta(2) integrin receptors such as phagocytosis and T cell activation. (PMID:16774752)
• Cathepsin K is essential for normal bone resorption (review) (PMID:16831915)
• CTSK may be involved in the pathogenesis of obesity by promoting adipocyte differentiation. (PMID:16912123)
• Possiable role in homeostasis of dermal extracellular matrix and dynamic equilibrium between matrix synthesis and proteolytic degradation, by counteracting deposition of matrix proteins during scar formation with its matrix-degrading activity. (PMID:16946716)
• analysis of human cathepsins K, L, and S iunteractions with elastins (PMID:17227755)
• Cathepsin K is constitutively expressed in normal human brain, and is alterated in its expression inscizophrenia. (PMID:17230547)
• molecular characterization of 12 unrelated patients with Pycnodysostosis; mutational profile consisted of 12 different mutations, including nine previously unreported ones (PMID:17397052)
• Cathepsin K expression is of predictive prognostic value for patients with high-grade osteosaromas and metastasis at diagnosis. (PMID:17683065)
• In breast cancer patients, cathepsin K serum levels were significantly lower than in sex matched control group or in patients with primary osteoporosis (PMID:17728092)
• in peri-and postmenopausal women, moderate negative correlation of serum cathepsin K levels with change in femoral neck BMD, but none with change in spinal BMD was found (PMID:17882010)
• Induction of cathepsin K is associated with the activation of protein p38 MAP kinase. (PMID:17991740)
• Myeloma-osteoclast interactions stimulated the production of TRAP, cathepsin K, MMP-1, -9, and uPA (PMID:18053985)
• did not detect any plasminogen degradation by cathepsins B, K and L. (PMID:18163891)
• catK may play an important role in melanoma invasion and metastasis by mediating intracellular degradation of matrix proteins after phagocytosis (PMID:18368130)
• cathepsin K is involved in the cleavage of type II collagen in human articular cartilage in certain OA patients and that it may play a role in both OA pathophysiology and the aging process. (PMID:18511517)
• Cathepsin X causes cytoskeletal rearrangements and stimulates migration of T lymphocytes. (PMID:18664495)
• Comparison of the S2 site between rat and human cathepsin K sequences indicated that two S2 residues at Ser134 and Val160 in rat are varied to Ala and Leu, respectively, in the human enzyme. (PMID:18664521)
• crystal structure of a 1:n complex of cathepsin K:chondroitin 4-sulfate (PMID:18692071)
• CTSK may function as a paracrine factor in breast tumorigenesis. (PMID:18765527)
• cathepsin B, cathepsin H, cathepsin X and cystatin C may have roles in inflammatory breast cancer (PMID:18949742)
• incomplete inactivation may partially explain why active cysteine cathepsins are still found during acute lung inflammation (PMID:18979635)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsk	ENSDARG00000040251
mus_musculus	Ctsk	ENSMUSG00000028111
rattus_norvegicus	Ctsk	ENSRNOG00000021155
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), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Protein

Protein identifiers

Cathepsin K — P43235 (reviewed: P43235)

Alternative names: Cathepsin O, Cathepsin O2, Cathepsin X

All UniProt accessions (10): P43235, A0A7I2V2M6, A0A7I2V354, A0A7I2V4B1, A0A7I2V4B6, A0A7I2V5Y6, A0A7I2V5Y9, A0A7I2V617, A0A7I2YQX0, Q5QP40

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Involved in the release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen.

Subcellular location. Lysosome. Secreted. Apical cell membrane.

Tissue specificity. Predominantly expressed in osteoclasts (bones). Expressed in thyroid epithelial cells.

Disease relevance. Pycnodysostosis (PKND) [MIM:265800] A rare autosomal recessive bone disorder characterized by deformity of the skull, maxilla and phalanges, osteosclerosis, and fragility of bone. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase C1 family.

RefSeq proteins (1): NP_000387* (*=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 3.4.22.38 — cathepsin K (BRENDA: 14 organisms, 203 substrates, 1116 inhibitors, 63 Km, 63 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
Z-LEU-ARG-7-AMIDO-4-METHYLCOUMARIN	0.002–0.0133	9
Z-GLY-PRO-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0034–0.048	8
CARBOBENZYLOXY-LEU-ARG-4-METHYLCOUMARYL-7-AMIDE	0.005–0.293	5
BENZYLOXYCARBONYL-PHE-ARG-7-AMIDO-4-METHYLCOUMAR	0.0051–0.021	4
BENZYLOXYCARBONYL-GLY-PRO-ARG-7-AMIDO-4-METHYLCO	0.0174–0.036	3
BENZYLOXYCARBONYL-LEU-LEU-ARG 4-METHYLCOUMARIN 7	0.0004–0.013	3
Z-PHE-ARG-7-AMIDO-4-METHYLCOUMARIN	0.005–0.0192	3
BENZYLOXYCARBONYL-LEU-ARG 4-METHYLCOUMARIN 7-AMI	0.0038–0.0083	2
BENZYLOXYCARBONYL-LEU-ARG-7-AMIDO-4-METHYLCOUMAR	0.0026–0.0133	2
BENZYLOXYCARBONYL-PHE-ARG 4-METHYLCOUMARIN 7-AMI	0.0075–0.058	2
BENZYLOXYCARBONYL-VAL-ARG 4-METHYLCOUMARIN 7-AMI	0.0131–0.033	2
BENZYLOXYCARBONYL-VAL-VAL-ARG 4-METHYLCOUMARIN 7	0.0185–0.044	2
BENZYLOXYCARBONYL-VAL-VAL-ARG-7-AMIDO-4-METHYLCO	0.0032–0.0077	2
CBZ-PHE-ARG-4-METHYLCOUMARIN 7-AMIDE	0.019–0.036	2
ACETYL-PHE-ARG 4-METHYLCOUMARIN 7-AMIDE	0.16	1

UniProt features (48 total): helix 14, strand 13, sequence variant 6, turn 4, active site 3, disulfide bond 3, signal peptide 1, propeptide 1, sequence conflict 1, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

70 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4X6H	X-RAY DIFFRACTION	1
5TDI	X-RAY DIFFRACTION	1.4
6ASH	X-RAY DIFFRACTION	1.42
3KWZ	X-RAY DIFFRACTION	1.49
6QLM	X-RAY DIFFRACTION	1.5
3KX1	X-RAY DIFFRACTION	1.51
7QBN	X-RAY DIFFRACTION	1.55
4X6J	X-RAY DIFFRACTION	1.59
5JA7	X-RAY DIFFRACTION	1.61
5TUN	X-RAY DIFFRACTION	1.62
4DMY	X-RAY DIFFRACTION	1.63
3O1G	X-RAY DIFFRACTION	1.65
4DMX	X-RAY DIFFRACTION	1.7
6QBS	X-RAY DIFFRACTION	1.7
7NXM	X-RAY DIFFRACTION	1.72
1TU6	X-RAY DIFFRACTION	1.75
5JH3	X-RAY DIFFRACTION	1.75
1MEM	X-RAY DIFFRACTION	1.8
3C9E	X-RAY DIFFRACTION	1.8
3KW9	X-RAY DIFFRACTION	1.8
3O0U	X-RAY DIFFRACTION	1.8
4YVA	X-RAY DIFFRACTION	1.8
6QL8	X-RAY DIFFRACTION	1.8
7NXL	X-RAY DIFFRACTION	1.8
6PXF	X-RAY DIFFRACTION	1.85
4X6I	X-RAY DIFFRACTION	1.87
7QBM	X-RAY DIFFRACTION	1.88
6QM0	X-RAY DIFFRACTION	1.9
7QBO	X-RAY DIFFRACTION	1.9
5Z5O	X-RAY DIFFRACTION	1.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43235-F1	94.89	0.91

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; 276; 296

Disulfide bonds (3): 136–177, 170–210, 269–318

Glycosylation sites (1): 103

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1592389	Activation of Matrix Metalloproteinases
R-HSA-1679131	Trafficking and processing of endosomal TLR
R-HSA-2132295	MHC class II antigen presentation
R-HSA-8939242	RUNX1 regulates transcription of genes involved in differentiation of keratinocytes
R-HSA-1280218	Adaptive Immune System
R-HSA-1474244	Extracellular matrix organization
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1

MSigDB gene sets: 588 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, MODULE_172, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, chr4q32, GOBP_CARTILAGE_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, NKX25_02, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE

GO Biological Process (9): mitophagy (GO:0000423), proteolysis (GO:0006508), thyroid hormone generation (GO:0006590), extracellular matrix disassembly (GO:0022617), collagen catabolic process (GO:0030574), bone resorption (GO:0045453), obsolete proteolysis involved in protein catabolic process (GO:0051603), negative regulation of cartilage development (GO:0061037), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886)

GO Molecular Function (9): fibronectin binding (GO:0001968), cysteine-type endopeptidase activity (GO:0004197), serine-type endopeptidase activity (GO:0004252), collagen binding (GO:0005518), cysteine-type peptidase activity (GO:0008234), proteoglycan binding (GO:0043394), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), lysosome (GO:0005764), external side of plasma membrane (GO:0009897), apical plasma membrane (GO:0016324), endolysosome lumen (GO:0036021), lysosomal lumen (GO:0043202), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Degradation of the extracellular matrix	2
Immune System	2
Extracellular matrix organization	1
Toll-like Receptor Cascades	1
Adaptive Immune System	1
Transcriptional regulation by RUNX1	1
Innate Immune System	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	2
endopeptidase activity	2
autophagy of mitochondrion	1
macroautophagy	1
protein metabolic process	1
thyroid hormone metabolic process	1
cellular component disassembly	1
extracellular matrix organization	1
catabolic process	1
collagen metabolic process	1
tissue homeostasis	1
bone remodeling	1
negative regulation of developmental process	1
cartilage development	1
negative regulation of multicellular organismal process	1
regulation of cartilage development	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
cysteine-type peptidase activity	1
serine-type peptidase activity	1
protein-containing complex binding	1
peptidase activity	1
carbohydrate derivative binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
lytic vacuole	1
plasma membrane	1
cell surface	1
side of membrane	1
apical part of cell	1
plasma membrane region	1
endosome lumen	1
endolysosome	1
lysosomal lumen	1
lysosome	1
vacuolar lumen	1

Protein interactions and networks

STRING

2751 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSK	ACP5	P13686	913
CTSK	NFATC1	O95644	898
CTSK	TNFSF11	O14788	891
CTSK	DCSTAMP	Q9H295	881
CTSK	CALCR	P30988	823
CTSK	TFE3	P19532	810
CTSK	TLR4	O00206	802
CTSK	CA2	P00918	791
CTSK	MMP9	P14780	787
CTSK	ATP6V0D2	Q8N8Y2	786
CTSK	OSCAR	Q8IYS5	772
CTSK	BGLAP	P02818	768
CTSK	SPP1	P10451	756
CTSK	TFEB	P19484	753
CTSK	RUNX2	Q13950	750

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CTSK	CTSV	psi-mi:“MI:0914”(association)	0.530
	CTSK	psi-mi:“MI:0407”(direct interaction)	0.410
srp-6	CTSK	psi-mi:“MI:0915”(physical association)	0.400
CTSK	POTEF	psi-mi:“MI:0914”(association)	0.350
ATF3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CTNNA1	MYO1G	psi-mi:“MI:0914”(association)	0.350
FOS	TMEM223	psi-mi:“MI:0914”(association)	0.350
GATA2	C11orf98	psi-mi:“MI:0914”(association)	0.350
	CTSK	psi-mi:“MI:0915”(physical association)	0.000
FGFR3	CTSK	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): ARID4B (Affinity Capture-MS), ERBB2IP (Affinity Capture-MS), CTSV (Affinity Capture-MS), C18orf25 (Affinity Capture-MS), ARID4B (Affinity Capture-MS), CTSL (Affinity Capture-MS), C18orf25 (Affinity Capture-MS), CTSV (Affinity Capture-MS), ERBB2IP (Affinity Capture-MS), CTSK (Affinity Capture-MS), CTSK (Two-hybrid), CTSK (Reconstituted Complex), S (Biochemical Activity), CTSK (Affinity Capture-RNA), ERBB2IP (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

4 interactions.

A	Effect	B	Mechanism
Odanacatib	down-regulates	CTSK	“chemical inhibition”
IL1B	“up-regulates quantity by expression”	CTSK	“transcriptional regulation”
TNF	“up-regulates quantity by expression”	CTSK	“transcriptional regulation”
CTSK	up-regulates	ECM_disassembly

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	69
Uncertain significance	159
Likely benign	178
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071759	NM_000396.4(CTSK):c.158del (p.Asn53fs)	Pathogenic
1072521	NM_000396.4(CTSK):c.377_378del (p.Tyr126fs)	Pathogenic
1073384	NM_000396.4(CTSK):c.429del (p.Ser144fs)	Pathogenic
1073792	NM_000396.4(CTSK):c.493del (p.Gln165fs)	Pathogenic
1074521	NM_000396.4(CTSK):c.609del (p.Pro202_Tyr203insTer)	Pathogenic
1332709	NM_000396.4(CTSK):c.399+1G>A	Pathogenic
1332837	NM_000396.4(CTSK):c.120+1G>T	Pathogenic
1382279	NM_000396.4(CTSK):c.253G>T (p.Glu85Ter)	Pathogenic
1443731	NM_000396.4(CTSK):c.653del (p.Ala218fs)	Pathogenic
1457491	NC_000001.10:g.(?150776487)(150779291_?)del	Pathogenic
1685684	NM_000396.4(CTSK):c.83dup (p.Trp29fs)	Pathogenic
1923939	NM_000396.4(CTSK):c.890+1G>A	Pathogenic
2017244	NM_000396.4(CTSK):c.1A>G (p.Met1Val)	Pathogenic
2202840	NM_000396.4(CTSK):c.580G>A (p.Gly194Ser)	Pathogenic
2687837	NM_000396.4(CTSK):c.150G>A (p.Trp50Ter)	Pathogenic
2692807	NM_000396.4(CTSK):c.600del (p.Tyr201fs)	Pathogenic
2815717	NM_000396.4(CTSK):c.908del (p.Gly303fs)	Pathogenic
2881118	NM_000396.4(CTSK):c.135dup (p.Arg46fs)	Pathogenic
3019488	NM_000396.4(CTSK):c.529del (p.Cys177fs)	Pathogenic
3247892	NC_000001.10:g.(?150771624)(150772205_?)del	Pathogenic
3247893	NC_000001.10:g.(?150769275)(150772205_?)del	Pathogenic
3614250	NM_000396.4(CTSK):c.915del (p.Gly306fs)	Pathogenic
3642902	NM_000396.4(CTSK):c.109_113del (p.Tyr37fs)	Pathogenic
370473	NM_000396.4(CTSK):c.426del (p.Phe142fs)	Pathogenic
371447	NM_000396.4(CTSK):c.120+1G>A	Pathogenic
3720241	NM_000396.4(CTSK):c.87G>A (p.Trp29Ter)	Pathogenic
4740157	NM_000396.4(CTSK):c.372del (p.Gly125fs)	Pathogenic
4818303	NM_000396.4(CTSK):c.282dup (p.Val95fs)	Pathogenic
623333	NM_000396.4(CTSK):c.891-1G>T	Pathogenic
684727	NM_000396.4(CTSK):c.905G>A (p.Trp302Ter)	Pathogenic

SpliceAI

2196 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150796894:CCCAG:C	acceptor_gain	1.0000
1:150796895:CCAG:C	acceptor_gain	1.0000
1:150796895:CCAGC:C	acceptor_gain	1.0000
1:150796896:CAGC:C	acceptor_gain	1.0000
1:150799538:TCTTA:T	donor_loss	1.0000
1:150799539:CTTAC:C	donor_loss	1.0000
1:150799540:TTA:T	donor_loss	1.0000
1:150799541:TA:T	donor_loss	1.0000
1:150799543:C:CT	donor_loss	1.0000
1:150805855:GAGTA:G	donor_loss	1.0000
1:150805856:AGTAC:A	donor_loss	1.0000
1:150805857:GTACC:G	donor_loss	1.0000
1:150805859:A:AG	donor_loss	1.0000
1:150805884:AT:A	donor_gain	1.0000
1:150806012:CTGGT:C	acceptor_gain	1.0000
1:150806013:TGGT:T	acceptor_gain	1.0000
1:150806016:TC:T	acceptor_loss	1.0000
1:150806017:C:CC	acceptor_gain	1.0000
1:150806017:CTA:C	acceptor_loss	1.0000
1:150806703:T:TA	donor_gain	1.0000
1:150808209:GTTAC:G	donor_loss	1.0000
1:150808210:TTA:T	donor_loss	1.0000
1:150808213:CCTG:C	donor_gain	1.0000
4:155928350:C:A	donor_gain	1.0000
4:155928707:A:T	acceptor_gain	1.0000
4:155929706:C:CC	acceptor_gain	1.0000
4:155929710:C:CT	acceptor_gain	1.0000
4:155939366:GTCAC:G	donor_loss	1.0000
4:155939367:TCA:T	donor_loss	1.0000
4:155939368:CACCT:C	donor_loss	1.0000

AlphaMissense

2172 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150799184:A:G	W292R	0.998
1:150799184:A:T	W292R	0.998
1:150804210:G:C	S143R	0.998
1:150804210:G:T	S143R	0.998
1:150804212:T:G	S143R	0.998
1:150804219:C:A	W140C	0.998
1:150804219:C:G	W140C	0.998
1:150804221:A:G	W140R	0.998
1:150804221:A:T	W140R	0.998
1:150796883:C:A	W302C	0.997
1:150796883:C:G	W302C	0.997
1:150796895:C:A	W298C	0.997
1:150796895:C:G	W298C	0.997
1:150799170:G:C	N296K	0.997
1:150799170:G:T	N296K	0.997
1:150799173:T:A	K295N	0.997
1:150799173:T:G	K295N	0.997
1:150799182:C:A	W292C	0.997
1:150799182:C:G	W292C	0.997
1:150799624:A:G	L235P	0.997
1:150804150:A:C	S163R	0.997
1:150804150:A:T	S163R	0.997
1:150804152:T:G	S163R	0.997
1:150806205:C:G	R47P	0.997
1:150799594:A:T	V245D	0.996
1:150799616:C:G	A238P	0.996
1:150804130:C:G	C170S	0.996
1:150804131:A:T	C170S	0.996
1:150804144:C:A	Q165H	0.996
1:150804144:C:G	Q165H	0.996

dbSNP variants (sampled 300 via entrez): RS1000036561 (1:150803082 G>A), RS1000086844 (1:150802663 C>T), RS1000100388 (1:150808383 T>G), RS1000301497 (1:150802465 C>G), RS1000986315 (1:150796614 T>C), RS1001260173 (1:150798705 A>T), RS1001334922 (1:150797170 T>G), RS1001587755 (1:150803715 G>C), RS1002020676 (1:150800903 A>G), RS1002198693 (1:150808878 A>C), RS1002261277 (1:150800554 T>C), RS1002531815 (1:150806353 T>C), RS1002655651 (1:150809197 G>T), RS1002691201 (1:150797290 T>C), RS1002925379 (1:150806070 G>A,T)

Disease associations

OMIM: gene MIM:601105 | disease phenotypes: MIM:265800

GenCC curated gene-disease

Disease	Classification	Inheritance
pycnodysostosis	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pycnodysostosis	Definitive	AR

Mondo (5): pycnodysostosis (MONDO:0009940), dental enamel hypoplasia (MONDO:0004038), periodontitis (MONDO:0005076), scoliosis (MONDO:0005392), skeletal dysplasia (MONDO:0018230)

Orphanet (2): Pycnodysostosis (Orphanet:763), Primary bone dysplasia (Orphanet:364526)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000269	Prominent occiput
HP:0000270	Delayed cranial suture closure
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000444	Convex nasal ridge
HP:0000448	Prominent nose
HP:0000486	Strabismus
HP:0000520	Proptosis
HP:0000539	Abnormality of refraction
HP:0000592	Blue sclerae
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000680	Delayed eruption of primary teeth
HP:0000689	Dental malocclusion
HP:0000696	Delayed eruption of permanent teeth
HP:0000707	Abnormality of the nervous system
HP:0000774	Narrow chest
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000889	Abnormal clavicle morphology
HP:0001156	Brachydactyly
HP:0001382	Joint hypermobility
HP:0001433	Hepatosplenomegaly
HP:0001511	Intrauterine growth retardation
HP:0001597	Abnormal nail morphology
HP:0001601	Laryngomalacia
HP:0001773	Short foot

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000492_2	Speech perception in dyslexia	5.000000e-08
GCST001266_1	Melanoma	9.000000e-11
GCST001966_1	Rhegmatogenous retinal detachment	1.000000e-07
GCST003419_2	Congenital left-sided heart lesions	9.000000e-07
GCST005951_38	Body mass index	4.000000e-09
GCST007930_19	Medication use (agents acting on the renin-angiotensin system)	1.000000e-08
GCST009356_2	Nonsyndromic cleft palate	2.000000e-08
GCST009357_15	Nonsyndromic cleft lip	1.000000e-06
GCST010278_4	Hand grip strength (Mahalanobis distance)	5.000000e-06
GCST012137_1	Motor coordination	8.000000e-06
GCST90011899_72	Aspartate aminotransferase levels	2.000000e-18

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004336	speech perception
EFO:0004340	body mass index
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0003959	cleft lip
EFO:0006941	grip strength measurement
EFO:0010749	motor function measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003744	Dental Enamel Hypoplasia	C07.650.800.295.625; C07.793.700.295.625; C16.131.850.800.295.625
D010518	Periodontitis	C07.465.714.533
D058631	Pycnodysostosis	C05.116.099.708.779; C16.320.565.595.800; C16.320.812; C18.452.648.595.800
D012600	Scoliosis	C05.116.900.800.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL2111361 (SELECTIVITY GROUP), CHEMBL2111368 (SELECTIVITY GROUP), CHEMBL2111380 (SELECTIVITY GROUP), CHEMBL2111396 (SELECTIVITY GROUP), CHEMBL2111441 (SELECTIVITY GROUP), CHEMBL268 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,431 (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
CHEMBL481611	ODANACATIB	3	804
CHEMBL203665	RELACATIB	2	115
CHEMBL371064	BALICATIB	2	97
CHEMBL5095230	ATUZAGINSTAT	2	72
CHEMBL5591580	IBUZATRELVIR	2	20

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 (10 total), top 10:

Ligand	Action	Affinity	Parameter
calpeptin	Inhibition	9.96	pIC50
odanacatib	Inhibition	9.7	pIC50
L873724	Inhibition	9.7	pIC50
relacatib	Inhibition	9.39	pKi
compound 23 [PMID: 35944849]	Inhibition	9.3	pIC50
balicatib	Inhibition	8.85	pIC50
compound 1b [PMID: 16290936]	Inhibition	8.74	pKi
GC-376	Inhibition	7.59	pIC50
UAWJ9-36-3	Inhibition	7.38	pIC50
K11777	Inhibition	6.4	pKi

Binding affinities (BindingDB)

707 measured of 925 human assays (925 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-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
(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
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[4-(pyrrolidin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.3 nM
N-[(1S)-2-[(3aS,6S,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-(4-methylpiperazin-1-yl)benzamide	KI	0.35 nM	US-8501744: Piperazine compounds
N-[(1S)-2-[(3aS,6S,6aR)-6-ethyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-(4-methylpiperazin-1-yl)benzamide	KI	0.4 nM	US-8501744: Piperazine compounds
N-[(2S)-1-[(3aS,6R,6aR)-6-(difluoromethyl)-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.45 nM	US-8501744: Piperazine compounds
N-[(1S)-2-[(3aS,6S,6aR)-3-oxo-6-propan-2-yl-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-(4-methylpiperazin-1-yl)benzamide	KI	0.45 nM	US-8501744: Piperazine compounds
N-[(2S)-1-[(3aS,6S,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.6 nM	US-8501744: Piperazine compounds
N-[(1S)-2-[(3aS,6R,6aR)-6-ethynyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.6 nM	US-8735395: Protease inhibitors
N-[(1S)-1-cyclopentyl-2-[(6R)-6-ethynyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-2-oxoethyl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.6 nM	US-9200006: Protease inhibitors
benzyl N-[(1S)-1-({1-[(2S)-2-{(benzyloxy)carbonylamino}-4-methylpentanoyl]-4-oxopyrrolidin-3-yl}carbamoyl)-3-methylbutyl]carbamate	KI	0.6 nM
N-[(2S)-1-[(3aS,6R,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.7 nM	US-8501744: Piperazine compounds
N-[(2S)-1-[(3aS,6S,6aR)-6-(difluoromethyl)-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.7 nM	US-8501744: Piperazine compounds
N—((S)-2-((3aS,6S,6aS)-6-chloro-3-oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(pyridin-3-yl)thiophene-2-carboxamide	KI	0.7 nM	US-9802947: 3-oxo-tetrahydro-furo[3,2-b]pyrrol-4(5H)-yl) derivatives II
N-[(2S)-1-[(3aS,6S,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	0.75 nM	US-8501744: Piperazine compounds
2-cyano-4-(cyclohexylamino)-N-{2-[4-(pyrrolidin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.75 nM
N-[(2S)-1-[(3aS,6S,6aR)-6-(difluoromethyl)-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	0.8 nM	US-8501744: Piperazine compounds
N-[(2S)-1-[(3aS,6S,6aR)-6-ethyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	0.8 nM	US-8501744: Piperazine compounds
N-[(2S)-1-[(3aS,6S,6aR)-3-oxo-6-propan-2-yl-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	0.8 nM	US-8501744: Piperazine compounds
N—((S)-2-((3aS,6S,6aS)-6-chloro-3-oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(pyridin-4-yl)thiophene-2-carboxamide	KI	0.8 nM	US-9802947: 3-oxo-tetrahydro-furo[3,2-b]pyrrol-4(5H)-yl) derivatives II
N-[(1S)-2-[(3aS,6R,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-(4-methylpiperazin-1-yl)benzamide	KI	1 nM	US-8501744: Piperazine compounds
N-((S)-2-((3aS,6S,6aS)-6-chloro-3- oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)- 1-cyclohexyl-2-oxoethyl)-5-(2-ethylpyridin-4- yl)thiophene-2-carboxamide	KI	1 nM	US-9725459: 3-oxo-tetrahydro-furo[3,2-B]pyrrol-4(5H)-yl) derivatives I
N-[(2S)-1-[(3aS,6S,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-3,3-dimethyl-1-oxobutan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	1.1 nM	US-8501744: Piperazine compounds
N-[(2S)-1-[(3aS,6R,6aR)-6-ethynyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	1.1 nM	US-8735395: Protease inhibitors
N-[(1S)-2-[(3aS,6R,6aR)-6-ethyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-(4-methylpiperazin-1-yl)benzamide	KI	1.2 nM	US-8501744: Piperazine compounds
(2S)-2-(1-benzofuran-2-ylformamido)-4-methyl-N-[(4R,7R)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)azepan-4-yl]pentanamide	KI	1.4 nM
N-[(2S,3S)-1-[(3aS,6R,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-3-methyl-1-oxopentan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	1.5 nM	US-8501744: Piperazine compounds
N-[(1S)-2-[(3aS,6R,6aR)-3-oxo-6-propan-2-yl-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-(4-methylpiperazin-1-yl)benzamide	KI	1.5 nM	US-8501744: Piperazine compounds
N—((S)-2-((3aS,6S,6aS)-6-chloro-3-oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(pyridazin-3-yl)thiophene-2-carboxamide	KI	1.5 nM	US-9802947: 3-oxo-tetrahydro-furo[3,2-b]pyrrol-4(5H)-yl) derivatives II
N-[(2S)-1-[(3aS,6R,6aR)-6-ethynyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	1.6 nM	US-8735395: Protease inhibitors
N-[(2S)-1-[(3aS,6R,6aR)-6-(difluoromethyl)-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	1.7 nM	US-8501744: Piperazine compounds
N—((S)-2-((3aS,6S,6aS)-6-chloro-3-oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(pyridazin-4-yl)thiophene-2-carboxamide	KI	1.8 nM	US-9802947: 3-oxo-tetrahydro-furo[3,2-b]pyrrol-4(5H)-yl) derivatives II
benzyl N-[(1S)-1-({1-[(2S)-2-{(benzyloxy)carbonylamino}-4-methylpentanoyl]-3-oxopiperidin-4-yl}carbamoyl)-3-methylbutyl]carbamate	KI	1.9 nM
5-amino-4-(bicyclo[2.2.1]heptan-2-ylamino)-6-morpholinopyrimidine-2-carbonitrile	IC50	2 nM
N—((S)-2-((3aS,6S,6aS)-6-chloro-3-oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(pyrimidin-5-yl)thiophene-2-carboxamide	KI	2.1 nM	US-9802947: 3-oxo-tetrahydro-furo[3,2-b]pyrrol-4(5H)-yl) derivatives II
N—((S)-2-((3aS,6S,6aS)-6-chloro-3-oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(pyrazin-2-yl)thiophene-2-carboxamide	KI	2.1 nM	US-9802947: 3-oxo-tetrahydro-furo[3,2-b]pyrrol-4(5H)-yl) derivatives II
N-[(2S)-1-[(3aS,6R,6aR)-6-methyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-(4-methylpiperazin-1-yl)benzamide	KI	2.5 nM	US-8501744: Piperazine compounds
(2S)-2-(1-benzofuran-2-ylformamido)-4-methyl-N-[(4S,7S)-7-methyl-3-oxo-1-(pyridine-2-sulfonyl)azepan-4-yl]pentanamide	KI	2.5 nM
N-[(2S)-1-[(6R)-6-(2,2-dibromoethenyl)-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	2.6 nM	US-9200006: Protease inhibitors
N-[(2S)-1-[(3aS,6R,6aR)-6-(2-methylprop-1-enyl)-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-4-methyl-1-oxopentan-2-yl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	2.7 nM	US-8735395: Protease inhibitors

ChEMBL bioactivities

2562 potent at pChembl≥5 of 2715 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL386506
10.96	IC50	0.011	nM	CHEMBL374890
10.96	IC50	0.011	nM	CHEMBL414530
10.96	Ki	0.011	nM	CHEMBL1651354
10.89	IC50	0.013	nM	CHEMBL449096
10.82	IC50	0.015	nM	CHEMBL480317
10.77	Ki	0.017	nM	CHEMBL1651355
10.72	Ki	0.019	nM	CHEMBL371420
10.66	IC50	0.022	nM	CHEMBL218024
10.66	Ki	0.022	nM	CHEMBL1651350
10.60	IC50	0.025	nM	CHEMBL220760
10.60	IC50	0.02512	nM	CHEMBL191584
10.59	IC50	0.0257	nM	CHEMBL190053
10.54	IC50	0.02884	nM	CHEMBL188400
10.51	IC50	0.031	nM	CHEMBL436303
10.49	Ki	0.032	nM	CHEMBL191558
10.49	Ki	0.032	nM	CHEMBL1651361
10.39	Ki	0.041	nM	RELACATIB
10.35	Ki	0.045	nM	CHEMBL1651349
10.33	IC50	0.047	nM	CHEMBL219536
10.32	IC50	0.048	nM	CHEMBL183812
10.19	Ki	0.064	nM	CHEMBL608115
10.15	Ki	0.071	nM	CHEMBL1651352
10.14	IC50	0.07244	nM	CHEMBL234367
10.14	Ki	0.072	nM	CHEMBL1651357
10.00	IC50	0.1	nM	CHEMBL203944
10.00	IC50	0.1	nM	CHEMBL382576
10.00	Ki	0.1	nM	CHEMBL284939
9.96	IC50	0.11	nM	CALPEPTIN
9.96	IC50	0.11	nM	CHEMBL4228926
9.96	Ki	0.11	nM	CHEMBL1651356
9.89	IC50	0.13	nM	CHEMBL114462
9.89	IC50	0.1288	nM	CHEMBL365822
9.85	Ki	0.14	nM	CHEMBL205172
9.85	Ki	0.14	nM	CHEMBL604281
9.80	Ki	0.16	nM	CHEMBL286364
9.80	Ki	0.16	nM	CHEMBL31674
9.80	IC50	0.16	nM	CHEMBL474438
9.80	Ki	0.16	nM	CHEMBL1651353
9.74	Ki	0.18	nM	ODANACATIB
9.74	Ki	0.18	nM	CHEMBL2028910
9.70	IC50	0.2	nM	CHEMBL182956
9.70	IC50	0.2	nM	CHEMBL204792
9.70	IC50	0.2	nM	CHEMBL381621
9.70	IC50	0.2	nM	CHEMBL207554
9.70	IC50	0.2	nM	CHEMBL437501
9.70	IC50	0.2	nM	CHEMBL437694
9.70	IC50	0.2	nM	CHEMBL1215628
9.70	IC50	0.2	nM	CHEMBL245580
9.70	IC50	0.2	nM	CHEMBL250501

PubChem BioAssay actives

2193 with measured affinity, of 3282 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)-4-methyl-1-[[(4S,5S)-5-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]-1-benzofuran-2-carboxamide	1797898: Enzyme Inhibition Assay from Article 10.1021/jm050915u: “Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.”	ki	<0.0001	uM
[(2S)-3,3-dimethyl-1-[4-[4-(trifluoromethyl)phenyl]pyrazol-1-yl]butan-2-yl] N-[(3S)-1,2-dioxo-1-(1H-pyrazol-5-ylamino)heptan-3-yl]carbamate	468523: Inhibition of human cathepsin K	ic50	<0.0001	uM
[(2S)-3,3-dimethyl-1-[4-[4-(trifluoromethyl)phenyl]imidazol-1-yl]butan-2-yl] N-[(3S)-1,2-dioxo-1-(1H-pyrazol-5-ylamino)heptan-3-yl]carbamate	468523: Inhibition of human cathepsin K	ic50	<0.0001	uM
[(2R)-3,3-dimethyl-1-[5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl]butan-2-yl] N-[(3S)-1,2-dioxo-1-(1H-pyrazol-5-ylamino)heptan-3-yl]carbamate	468523: Inhibition of human cathepsin K	ic50	<0.0001	uM
2-cyano-4-(cyclohexylamino)-N-[2-(4-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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-(4-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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[4-(4-methylpiperazin-1-yl)phenyl]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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[4-(2-imidazol-1-ylethoxy)phenyl]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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[3-(2-imidazol-1-ylethoxy)-4-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	<0.0001	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
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	<0.0001	uM
2-cyano-4-(cyclohexylamino)-N-[2-[4-(4-methylpiperazin-1-yl)phenyl]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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[3-(4-methylpiperazin-1-yl)phenyl]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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[4-(1-methylpiperidin-4-yl)oxyphenyl]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	<0.0001	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[3-(2-imidazol-1-ylethoxy)phenyl]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	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] 1-cyanoazetidine-2-carboxylate	241950: Inhibitory concentration against human cathepsin K using 10 uM Cbz-Phe-Arg-AMC	ic50	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(propan-2-yl)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(methyl)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[butyl(cyano)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[benzyl(cyano)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(ethyl)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-phenylbutan-2-yl] N-[cyano(methyl)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(propyl)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(2-methylpropyl)amino]carbamate	239258: Inhibition constant against human cathepsin K in fluorescence assay using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
N-[(2S)-1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]-4-(4-piperazin-1-ylphenyl)benzamide	342300: Inhibition of cathepsin K	ic50	<0.0001	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-phenylurea	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	<0.0001	uM
1-benzyl-3-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]urea	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	<0.0001	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	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	<0.0001	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	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric 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	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	<0.0001	uM
N-[(2S)-4-methyl-1-oxo-1-[[(4S)-3-oxo-1-[2-(3-pyridin-2-ylphenyl)acetyl]azepan-4-yl]amino]pentan-2-yl]-5-(2-morpholin-4-ylethoxy)-1-benzofuran-2-carboxamide	219369: Inhibition of Human cathepsin K	ki	<0.0001	uM
N-[(2S)-4-methyl-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]-1-benzofuran-2-carboxamide	1797898: Enzyme Inhibition Assay from Article 10.1021/jm050915u: “Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.”	ki	<0.0001	uM
(2S)-N-(cyanomethyl)-4-methyl-2-[[(1S)-2,2,2-trifluoro-1-[4-(2-fluorophenyl)phenyl]ethyl]amino]pentanamide	262994: Inhibition of humanized rabbit Cathepsin K	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	0.0001	uM
N-[(2S)-4-methyl-1-[[(4S,6S)-6-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]-1-benzofuran-2-carboxamide	1797898: Enzyme Inhibition Assay from Article 10.1021/jm050915u: “Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.”	ki	0.0001	uM
N-[(2S)-1-[(4-cyano-1,1-dioxothian-4-yl)amino]-4-methyl-1-oxopentan-2-yl]-4-phenylbenzamide	1391659: Inhibition of human cathepsin K	ic50	0.0001	uM
(2S)-N-(cyanomethyl)-4-methyl-2-[[(1S)-2,2,2-trifluoro-1-[4-(4-methoxyphenyl)phenyl]ethyl]amino]pentanamide	262994: Inhibition of humanized rabbit Cathepsin K	ic50	0.0001	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]carbamate	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	0.0001	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-1-oxo-3-phenylpropan-2-yl]carbamate	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	0.0001	uM
[(2S)-1-phenylbutan-2-yl] N-[(2S)-1-oxohexan-2-yl]carbamate	241950: Inhibitory concentration against human cathepsin K using 10 uM Cbz-Phe-Arg-AMC	ic50	0.0001	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-3-cyclohexyl-1-oxopropan-2-yl]carbamate	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	0.0001	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	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	0.0001	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	554256: Inhibition of human recombinant cathepsin K after 30 mins by spectrophotometric assay	ki	0.0001	uM
[(2R)-3,3-dimethyl-1-[5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl]butan-2-yl] N-[(3S)-1,2-dioxo-1-[(2-oxo-1,3-oxazolidin-3-yl)amino]heptan-3-yl]carbamate	468523: Inhibition of human cathepsin K	ic50	0.0001	uM
benzyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxohexan-2-yl]amino]pentan-2-yl]carbamate	48403: Inhibitory activity against recombinant human cathepsin K	ic50	0.0001	uM
(2S)-N-(cyanomethyl)-4-methyl-2-[[4-(4-piperazin-1-ylphenyl)thiophen-3-yl]amino]pentanamide	240722: Inhibitory concentration against human cathepsin K	ic50	0.0002	uM
(2S)-N-(cyanomethyl)-4-methyl-2-[[(1S)-2,2,2-trifluoro-1-(4-thiophen-3-ylphenyl)ethyl]amino]pentanamide	262994: Inhibition of humanized rabbit Cathepsin K	ic50	0.0002	uM
(2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-[[(1S)-2,2,2-trifluoro-1-[4-(4-methylsulfonylphenyl)phenyl]ethyl]amino]pentanamide	1402856: Inhibition of human cathepsin K	ki	0.0002	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression, affects expression, decreases expression	4
bisphenol A	affects expression, decreases methylation, increases expression	3
Cyclosporine	decreases expression, affects expression	3
chloropicrin	affects expression, decreases expression	2
Air Pollutants	increases abundance, decreases expression, affects expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	increases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
methylselenic acid	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide	increases cleavage, increases reaction	1
ochratoxin A	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
belinostat	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
N-butyrylglucosamine	increases expression	1
bisphenol S	increases expression	1
incobotulinumtoxinA	increases expression	1
bisphenol AF	increases expression	1
anagliptin	decreases reaction, increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Resveratrol	increases expression, affects cotreatment, decreases reaction	1

ChEMBL screening assays

376 unique, capped per target: 365 binding, 5 admet, 5 toxicity, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5106300	Binding	Selectivity ratio of IC50 for Cathepsin V (unknown origin) to IC50 for Cathepsin K (unknown origin)	Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis. — Bioorg Med Chem Lett
CHEMBL4040392	ADMET	Substrate activity at recombinant human cathepsin K expressed in Escherichia coli assessed as compound cleavage at 100 uM after 1 hr by HPLC analysis	Design, Synthesis, and Pharmacokinetics of a Bone-Targeting Dual-Action Prodrug for the Treatment of Osteoporosis. — J Med Chem
CHEMBL5154226	Toxicity	Inhibition of human cathepsin K using Ac-LR-AFC as substrate by FRET assay	Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06205420	PHASE4	COMPLETED	Injection Molding Technique: A Minimally Invasive Management for Enamel Hypoplasia Affecting Permanent Anterior Teeth in Children
NCT00296881	PHASE4	UNKNOWN	SRP in Combination With PERIOWAVE in Comparison to SRP Alone in Chronic Periodontitis
NCT00297518	PHASE4	COMPLETED	Study of Scaling and Root Planing (SRP) With PerioWave vs. SRP Alone in Chronic Periodontitis
NCT00297531	PHASE4	UNKNOWN	Study of Scaling and Root Planing With PerioWave Versus Scaling and Root Planing Alone in Chronic Periodontitis
NCT00668746	PHASE4	COMPLETED	Long-term Safety of Minocycline in Patients With Gum Disease
NCT00707369	PHASE4	COMPLETED	Adjunctive Antimicrobial Therapy of Periodontitis: Long-Term Effects on Disease Progression and Oral Microbiological Colonization
NCT01030666	PHASE4	TERMINATED	Effect of Postsurgical Systemic Doxycycline After Regenerative Periodontal Therapy
NCT01538927	PHASE4	COMPLETED	Effect of Fibrin Sealant on Early Wound Healing
NCT01548469	PHASE4	COMPLETED	Study to Evaluate Clinical Efficacy and Safety of Bio Mineral Toothpaste in Patients With Mild Periodontitis
NCT01593540	PHASE4	COMPLETED	Clinical Examination of Metal Free Interdental Brushes
NCT01806974	PHASE4	TERMINATED	Consequences of Anti-interleukin 6 Immunotherapy Treatment for Rheumatoid Arthritis on Periodontium
NCT02030470	PHASE4	COMPLETED	Evaluation of Photodynamic Treatment FOTOSAN® Efficacy in Periodontology
NCT02062047	PHASE4	COMPLETED	Full-mouth and Partial-mouth Scaling and Root Planing in Type 2 Diabetic Subjects
NCT02124655	PHASE4	COMPLETED	Antiplaque Effect of Essential Oils and 0.2% Chlorhexidine on an in Situ Model of Oral Biofilm Growth.
NCT02135952	PHASE4	UNKNOWN	Metronidazole and Amoxicillin for the Treatment of Type 2 Diabetic Subjects With Periodontitis
NCT02149758	PHASE4	COMPLETED	EFFECT OF SELECTIVE COX-2 INHIBITOR (ETORICOXIB) ALONG WITH SCALING AND ROOT PLANING (SRP) ON CLINICAL PARAMETERS AND SALIVARY LEVEL OF SUPEROXIDE DISMUTASE IN CHRONIC GENERALIZED PERIODONTITIS A DOUBLE-BLIND, PLACEBO-CONTROLLED, DOUBLE-MASKED RANDOMIZED CONTROLLED TRIAL (RCT).
NCT02215460	PHASE4	COMPLETED	Treatment of Periodontitis by Conventional 4 Weekly Sections or Within 24 Hours
NCT02215473	PHASE4	COMPLETED	Bacteremia in Periodontal Patients
NCT02267239	PHASE4	UNKNOWN	Methodology Antiseptic Application, Influence on Oral Biofilm.
NCT02359721	PHASE4	COMPLETED	Clarithromycin is an Adjunct to Scaling and Root Planing
NCT02470611	PHASE4	COMPLETED	Sodium Alendronate in Non Surgical Periodontal Therapy
NCT02794506	PHASE4	COMPLETED	Propolis Improves Glycemic Control in Subjects With Type 2 Diabetes and Chronic Periodontitis
NCT02921165	PHASE4	COMPLETED	Comparison of Topical Analgesic With Saline Rinses in Post Extraction Healing
NCT02946801	PHASE4	UNKNOWN	Antiplaque Effect of Essential Oils With and Without Alcochol on an in Situ Model of Oral Biofilm Growth
NCT03103204	PHASE4	COMPLETED	Treatment of Periodontitis in Obese Individuals
NCT03146390	PHASE4	UNKNOWN	Essential Oils With and Without Alcohol: Substantivity and Antiplaque Effect
NCT03176537	PHASE4	WITHDRAWN	Periodontal Profile of Hypogonadic Men
NCT03311906	PHASE4	COMPLETED	Evaluation of the Efficacy of 0.8% Hyaluronic Acid Gel
NCT03354312	PHASE4	COMPLETED	Acceptance and Preference of Lidocaine Gel Compared to Injection Anesthesia After Non Surgical Periodontal Treatment
NCT04027179	PHASE4	UNKNOWN	Tongue Dysbiosis Effects on Arterial Pressure of Periodontitis Patients
NCT04032132	PHASE4	COMPLETED	Curcumin Paste as an Adjunctive Therapy in Periodontitis
NCT04036890	PHASE4	COMPLETED	Local Minocycline in Patients Under Supportive Periodontal Therapy
NCT04044417	PHASE4	COMPLETED	Curcumin-Simvastatin-EDTA in the Treatment of Periodontitis
NCT04149405	PHASE4	COMPLETED	Alterations of GCF Levels of Sclerostin and DKK-1 in Postmenopausal Osteoporosis
NCT04178590	PHASE4	COMPLETED	Effect of Injectable Platelet-Rich Fibrin (i-PRF) in Initial Treatment of Chronic Periodontitis
NCT04223076	PHASE4	UNKNOWN	Clinical Effect of Chlorhexidine Mouthwash After Periodontal Surgery
NCT04353362	PHASE4	COMPLETED	Alternative Antibiotic Regimen in Periodontitis Treatment
NCT04964167	PHASE4	COMPLETED	Indocyanine-green Mediated Photosensitizer VS Aloe Vera Gel: Adjunct Therapy to Scaling and Root Planing in Patients With Chronic Periodontitis
NCT04983849	PHASE4	COMPLETED	Evaluation of Metronidazole Hydrogel 25% in Stage II and III Periodontitis
NCT05530252	PHASE4	COMPLETED	Effects of AMP Application After Non-surgical Periodontal Therapy on Treatment of Periodontitis