CTSL

Summary

CTSL (cathepsin L, HGNC:2537) is a protein-coding gene on chromosome 9q21.33, encoding Procathepsin L (P07711). Thiol protease important for the overall degradation of proteins in lysosomes.

The protein encoded by this gene is a lysosomal cysteine proteinase that plays a major role in intracellular protein catabolism. Its substrates include collagen and elastin, as well as alpha-1 protease inhibitor, a major controlling element of neutrophil elastase activity. The encoded protein has been implicated in several pathologic processes, including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria. This protein, which is a member of the peptidase C1 family, is a dimer composed of disulfide-linked heavy and light chains, both produced from a single protein precursor. Additionally, this protein cleaves the S1 subunit of the SARS-CoV-2 spike protein, which is necessary for entry of the virus into the cell.

Source: NCBI Gene 1514 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 62 total
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001912

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2537
Approved symbol	CTSL
Name	cathepsin L
Location	9q21.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ31037
Ensembl gene	ENSG00000135047
Ensembl biotype	protein_coding
OMIM	116880
Entrez	1514

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 38 protein_coding, 16 retained_intron, 7 nonsense_mediated_decay

ENST00000340342, ENST00000342020, ENST00000343150, ENST00000375894, ENST00000482054, ENST00000495822, ENST00000676466, ENST00000676480, ENST00000676531, ENST00000676576, ENST00000676769, ENST00000676881, ENST00000676909, ENST00000676946, ENST00000676961, ENST00000677019, ENST00000677262, ENST00000677345, ENST00000677349, ENST00000677523, ENST00000677615, ENST00000677638, ENST00000677761, ENST00000677821, ENST00000677864, ENST00000677935, ENST00000677955, ENST00000678259, ENST00000678367, ENST00000678442, ENST00000678596, ENST00000678599, ENST00000678649, ENST00000678654, ENST00000678752, ENST00000678965, ENST00000679025, ENST00000679028, ENST00000679030, ENST00000679141, ENST00000679149, ENST00000679157, ENST00000679252, ENST00000882604, ENST00000882605, ENST00000882606, ENST00000882607, ENST00000882608, ENST00000882609, ENST00000882610, ENST00000882611, ENST00000882612, ENST00000882613, ENST00000882614, ENST00000882615, ENST00000915605, ENST00000915606, ENST00000941021, ENST00000941022, ENST00000941023, ENST00000941024

RefSeq mRNA: 10 — MANE Select: NM_001912 NM_001257971, NM_001257972, NM_001257973, NM_001382757, NM_001382758, NM_001382766, NM_001382767, NM_001382768, NM_001912, NM_145918

CCDS: CCDS6675, CCDS94432, CCDS94433

Canonical transcript exons

ENST00000343150 — 8 exons

Exon	Start	End
ENSE00001886667	87726119	87726398
ENSE00001931704	87731008	87731469
ENSE00003469886	87728027	87728149
ENSE00003495030	87729573	87729735
ENSE00003520790	87727594	87727729
ENSE00003588895	87728585	87728809
ENSE00003636798	87728250	87728396
ENSE00003661419	87730381	87730498

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 208.0065 / max 3993.5149, expressed in 1741 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97232	206.1220	1740
97235	0.7326	284
97234	0.4683	215
205550	0.4647	231
97233	0.2189	98

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.42	gold quality
decidua	UBERON:0002450	98.80	gold quality
placenta	UBERON:0001987	98.78	gold quality
islet of Langerhans	UBERON:0000006	98.66	gold quality
omental fat pad	UBERON:0010414	98.41	gold quality
peritoneum	UBERON:0002358	98.40	gold quality
pericardium	UBERON:0002407	98.24	gold quality
gall bladder	UBERON:0002110	98.19	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.06	gold quality
upper lobe of left lung	UBERON:0008952	98.00	gold quality
endometrium epithelium	UBERON:0004811	97.99	gold quality
left uterine tube	UBERON:0001303	97.98	gold quality
renal medulla	UBERON:0000362	97.96	gold quality
upper lobe of lung	UBERON:0008948	97.94	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.91	gold quality
mucosa of stomach	UBERON:0001199	97.81	gold quality
smooth muscle tissue	UBERON:0001135	97.79	gold quality
right atrium auricular region	UBERON:0006631	97.77	gold quality
right ovary	UBERON:0002118	97.76	gold quality
body of uterus	UBERON:0009853	97.74	gold quality
type B pancreatic cell	CL:0000169	97.73	gold quality
calcaneal tendon	UBERON:0003701	97.70	gold quality
left ovary	UBERON:0002119	97.68	gold quality
layer of synovial tissue	UBERON:0007616	97.65	gold quality
right lung	UBERON:0002167	97.58	gold quality
adult mammalian kidney	UBERON:0000082	97.57	gold quality
left coronary artery	UBERON:0001626	97.56	gold quality
descending thoracic aorta	UBERON:0002345	97.54	gold quality
spleen	UBERON:0002106	97.52	gold quality
thoracic aorta	UBERON:0001515	97.45	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	5080.62
E-MTAB-10287	yes	4228.65
E-MTAB-8142	yes	2917.39
E-MTAB-7407	yes	2661.46
E-GEOD-84465	yes	2112.02
E-MTAB-9801	yes	1676.84
E-HCAD-1	yes	89.80
E-CURD-122	yes	72.09
E-MTAB-6678	yes	41.41
E-MTAB-10042	yes	28.32
E-HCAD-9	yes	23.19
E-CURD-112	yes	19.73
E-GEOD-130148	yes	19.52
E-MTAB-9467	yes	18.32
E-MTAB-9067	yes	7.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPG, EGR1, FOS, FOXO1, FOXO3, GLI2, JUN, PPARA, PPARG, SP1, SP2, SP3, STAT1, TP53

miRNA regulators (miRDB)

25 targeting CTSL, 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-4282	99.99	75.36	6408
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-6072	98.00	66.47	804
HSA-MIR-12127	97.93	66.67	793
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-3529-5P	97.12	67.06	440
HSA-MIR-6891-3P	95.80	65.76	683
HSA-MIR-548AD-3P	94.39	66.04	350
HSA-MIR-3713	94.12	60.05	70

Literature-anchored findings (GeneRIF, showing 40)

• cis-acting element on cathepsin L mRNA can be bound by a negative trans-acting regulator, thus leading to reduced expression rates (PMID:11767948)
• its activity resulted in extensive bone destruction in both cholesteatomas and noncholesteatomas of the middle ear (PMID:11771045)
• Characterization and comparative mapping of the porcine CTSL gene indicates a novel synteny between HSA9q21–>q22 and SSC10q11–>q12 (PMID:11978977)
• the subcellular distribution of cathepsin B, L, and S ativities underwent a shift from endosome to lysosome localization during monocyte differentiation in cell culture (PMID:12437117)
• suppression of cathepsin L expression in A549 cells leads to a growth inhibition which is partially compensated by an upregulation of IL-8 production. (PMID:12437119)
• cathepsin K and L processed high-molecular weight kininogen under stoichiometric conditions, only cathepsin L generated significant amounts of immunoreactive kinins. Cathepsin L exhibited higher specificity constants (kcat/Km) than tissue kallikrein (PMID:12492488)
• lack of involvement in degrading MHC class II-associated invariant chain in nonprofessional antigen-presenting cells (PMID:12748383)
• These results show that cathepsin L is secreted from human fibroblasts in response to external stimuli and plays an important role in IL-8 processing in inflammatory sites. (PMID:12818188)
• The expression of cathepsin L in non-small cell lung cancer is not related to the patients’ outcome at a statistically significant level. (PMID:12926111)
• insulin-stimulated cathepsin L expression in skeletal muscle is impaired in diabetic but not in nondiabetic monozygotic twins, suggesting that the changes may be secondary to impaired glucose metabolism. (PMID:12941783)
• Cathepsin L is released and catalytically active in T lymphocyte cytosol during supraoptimal activation-induced apoptosis of T cells in vitro and may participate in high dose tolerance in vivo. (PMID:15100281)
• endothelial cell-associated cathepsins B and L are not involved in the invasive growth of capillaries from existing blood vessels and the presence of collagen is necessary for MMP2 expression in endothelial cells (PMID:15255544)
• The function of cathepsin L (catL) in the proteolytic network of human lung epithelial cells and its role in the regulation of apoptosis. (PMID:15318816)
• serum level of cathepsin L can serve as a marker of bone resorption and bone density (PMID:15454886)
• Peptide fragment of p47 SEP is a reversible competitive inhibitor of cathepsin L. (PMID:15498563)
• Mechanical stress (compression and tension forces) causes an increase in secretion of cathepsins B and L in periodontal ligament cells in vitro. (PMID:15512772)
• Data suggest that cathepsin L has a critical role in the integration of circulating endothelial progenitor cells (EPC) into ischemic tissue and is required for EPC-mediated neovascularization. (PMID:15665831)
• cathepsins B and L have roles in atypical pituitary adenoma (PMID:15816632)
• cathepsin and inhibitor expression was not different between central and peripheral meningioma tissue or between histological subtypes of meningiomas with the exception of cathepsin L, the level of which was significantly lower in transitional meningiomas (PMID:15832773)
• cathepsin L is over-expressed in human AAA and atherosclerotic lesions and its expression in vascular cell types found in these lesions is regulated by pro-inflammatory cytokines. (PMID:15982660)
• The presence of active cathepsins L, K and S suggests that they contribute to the extracellular breakdown of the extracellular matrix. (PMID:16354158)
• highest expression of Cat L was found in psoriasis, atopic eczema and squamous cell carcinoma (PMID:16433682)
• Identification of CTSV & CTSL as targets for cystatin M/E, their (co)-expression in the stratum granulosum of skin, and activity of CTSL toward transglutaminase 3 strongly imply an important role for them in the differentiation process of human epidermis. (PMID:16565075)
• Results showed that the breast cancer cell line exhibiting the highest in vitro invasiveness also expressed the highest amount of cathepsin L splice variant L-A3. (PMID:16740135)
• CTSL is expressed in the brain of these compound mutants, predominantly in neurons of the cerebral cortex and in Purkinje cells of the cerebellum, where it appears to prevent neuronal cell death (PMID:16913838)
• the 32-kDa cathepsin L found in HT 1080 cell medium is involved in cancer invasion and metastasis (PMID:16918298)
• analysis of human cathepsins K, L, and S iunteractions with elastins (PMID:17227755)
• level of active cathepsin B and L is increased in tumors (PMID:17519890)
• Results describe the structure of chagasin in complex with the host cysteine protease, cathepsin L, at 1.75 A resolution. (PMID:17561110)
• over-expression of VEGF in human glioblastoma cells induces cathepsin L expression at the transcriptional level. This mechanism could be involved in the enhanced tumorogenic potential of these cells. (PMID:17574778)
• Results describe the participation of cathepsin L in adipogenesis and glucose intolerance. (PMID:17643114)
• Here we demonstrate a role for cathepsin L (CatL) cleavage of Ebola virus GP in the generation of a stable 18-kDa GP1 viral intermediate that exhibits increased binding to and infectivity for susceptible cell targets. (PMID:17928356)
• did not detect any plasminogen degradation by cathepsins B, K and L. (PMID:18163891)
• shortening the heavy-light chain loop does not change substrate affinity but does influence activity, in part via conformational change (PMID:18221013)
• These results indicated that in vivo a tumour hypoxic environment up-regulates cathepsin L expression which promotes tumour progression. (PMID:18366346)
• Cathepsin L has a role in processing and activation of proheparanase through multiple cleavages of a linker segment (PMID:18450756)
• cathepsin L is involved in death of macrophages, necrotic core formation and development of atherosclerotic plaque instability (PMID:18495127)
• blood levels are significantly elevated in patients with colorectal adenoma and colorectal carcinoma (PMID:18616803)
• Cathepsin L is required for invasion of endothelial progenitor cells (EPC) into ischemic tissue; thereby its reduction may limit the functional capacity of EPC to improve neovascularization in diabetics. (PMID:18619973)
• Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis. (PMID:18658137)

Cross-species orthologs

35 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsl.1	ENSDARG00000003902
danio_rerio	zgc:103438	ENSDARG00000035663
danio_rerio	si:dkey-267n13.1	ENSDARG00000035665
danio_rerio	ctss1	ENSDARG00000036940
danio_rerio	tinagl1	ENSDARG00000061231
danio_rerio	ctsf	ENSDARG00000063095
danio_rerio	zgc:110239	ENSDARG00000077664
danio_rerio	si:zfos-1897c11.1	ENSDARG00000077910
danio_rerio	si:dkey-183k8.2	ENSDARG00000089026
danio_rerio	si:dkey-228a15.1	ENSDARG00000095698
danio_rerio	zgc:123103	ENSDARG00000099200
danio_rerio	ctsbb	ENSDARG00000101051
drosophila_melanogaster	CtsB	FBGN0030521
drosophila_melanogaster	CtsL4	FBGN0032228
drosophila_melanogaster	CtsL2	FBGN0033874
drosophila_melanogaster	Swim	FBGN0034709
drosophila_melanogaster	CtsL3	FBGN0037396
drosophila_melanogaster	CtsK1	FBGN0250848
drosophila_melanogaster	CtsF	FBGN0260462
caenorhabditis_elegans		WBGENE00000781
caenorhabditis_elegans		WBGENE00000782
caenorhabditis_elegans		WBGENE00000784
caenorhabditis_elegans		WBGENE00000785
caenorhabditis_elegans	cpz-1	WBGENE00000788
caenorhabditis_elegans		WBGENE00007055
caenorhabditis_elegans	F26E4.3	WBGENE00009158
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), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Protein

Protein identifiers

Procathepsin L — P07711 (reviewed: P07711)

Alternative names: Cathepsin L1, Major excreted protein

All UniProt accessions (9): A0A7I2V2H7, A0A7I2V484, A0A7I2V5F7, A0A7I2V5M3, A0A7I2V601, A0A7I2YQA2, A0A7I2YQB5, P07711, Q5T8F0

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease important for the overall degradation of proteins in lysosomes. Plays a critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. Involved in the solubilization of cross-linked TG/thyroglobulin and in the subsequent release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen. In neuroendocrine chromaffin cells secretory vesicles, catalyzes the prohormone proenkephalin processing to the active enkephalin peptide neurotransmitter. In thymus, regulates CD4(+) T cell positive selection by generating the major histocompatibility complex class II (MHCII) bound peptide ligands presented by cortical thymic epithelial cells. Also mediates invariant chain processing in cortical thymic epithelial cells. Major elastin-degrading enzyme at neutral pH. Accumulates as a mature and active enzyme in the extracellular space of antigen presenting cells (APCs) to regulate degradation of the extracellular matrix in the course of inflammation. Secreted form generates endostatin from COL18A1. Critical for cardiac morphology and function. Plays an important role in hair follicle morphogenesis and cycling, as well as epidermal differentiation. Required for maximal stimulation of steroidogenesis by TIMP1. (Microbial infection) In cells lacking TMPRSS2 expression, facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via a slow acid-activated route with the proteolysis of coronavirus spike (S) glycoproteins in lysosome for entry into host cell. Proteolysis within lysosomes is sufficient to activate membrane fusion by coronaviruses SARS-CoV and EMC (HCoV-EMC) S as well as Zaire ebolavirus glycoproteins. Functions in the regulation of cell cycle progression through proteolytic processing of the CUX1 transcription factor. Translation initiation at downstream start sites allows the synthesis of isoforms that are devoid of a signal peptide and localize to the nucleus where they cleave the CUX1 transcription factor and modify its DNA binding properties.

Subunit / interactions. Dimer of a heavy and a light chain linked by disulfide bonds. Interacts with Long isoform of CD74/Ii chain; the interaction stabilizes the conformation of mature CTSL.

Subcellular location. Lysosome. Apical cell membrane. Cytoplasmic vesicle. Secretory vesicle. Chromaffin granule. Secreted. Extracellular space. Secreted Nucleus.

Post-translational modifications. During export along the endocytic pathway, pro-CTSL undergoes several proteolytic cleavages to generate the CTSL single-chain and two-chain mature forms, composed of a heavy chain linked to a light chain by disulfide bonds. Autocleavage; produces the single-chain CTSL after cleavage of the propeptide. The cleavage can be intermolecular.

Activity regulation. Inhibited by the propeptide produced by autocleavage. Long isoform of CD74/Ii chain stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of APCs. IFNG enhances the conversion into the CTSL mature and active form. Inhibited by CST6. Inhibited by the glycopeptide antibiotic teicoplanin. Inhibited by amantadine.

Similarity. Belongs to the peptidase C1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P07711-1	1	yes
P07711-3	2

RefSeq proteins (10): NP_001244900, NP_001244901, NP_001244902, NP_001369686, NP_001369687, NP_001369695, NP_001369696, NP_001369697, NP_001903, NP_666023 (=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 3.4.22.15 — cathepsin L (BRENDA: 65 organisms, 391 substrates, 936 inhibitors, 123 Km, 114 kcat entries)
• EC 3.4.22.43 — cathepsin V (BRENDA: 2 organisms, 70 substrates, 61 inhibitors, 19 Km, 19 kcat entries)
• EC 3.4.22.B49 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-PHE-ARG-4-METHYLCOUMARIN 7-AMI	0.0007–0.0342	13
BENZYLOXYCARBONYL-PHE-ARG-7-AMIDO-4-METHYLCOUMAR	0.0011–0.0157	9
BENZYLOXYCARBONYL-PHE-ARG-7-AMIDO-4-METHYLCOUMAR	0.0044–0.0069	7
L-PHE-L-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0003–0.0005	6
BENZYLOXYCARBONYL-L-PHE-L-ARG-7-AMIDO-4-METHYLCO	0.0057–0.0488	4
BENZYLOXYCARBONYL-GLY-PRO-ARG-7-AMIDO-4-METHYLCO	0.014–0.081	2
BENZYLOXYCARBONYL-LEU-ARG-7-AMIDO-4-METHYLCOUMAR	0.0013–0.0098	2
EFL-4-NITROANILIDE	0.2632–1.026	2
L-VAL-L-LEU-L-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0069–0.0124	2
VLK-4-NITROANILIDE	0.0061–0.0664	2
Z-PHE-ARG-4-METHYL-7-COUMARYL AMIDE	0.0041–0.0048	2
2-AMINOBENZOYL-ALA-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0004	1
2-AMINOBENZOYL-ARG-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0002	1
2-AMINOBENZOYL-ASN-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0007	1
2-AMINOBENZOYL-GLN-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0008	1

UniProt features (68 total): strand 17, helix 13, binding site 11, turn 6, site 4, chain 3, disulfide bond 3, active site 3, propeptide 2, sequence conflict 2, signal peptide 1, glycosylation site 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

64 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2XU3	X-RAY DIFFRACTION	0.9
5MAE	X-RAY DIFFRACTION	1
5MAJ	X-RAY DIFFRACTION	1
2XU4	X-RAY DIFFRACTION	1.12
5MQY	X-RAY DIFFRACTION	1.13
2YJC	X-RAY DIFFRACTION	1.14
2YJ2	X-RAY DIFFRACTION	1.15
3HHA	X-RAY DIFFRACTION	1.27
2YJ8	X-RAY DIFFRACTION	1.3
2YJ9	X-RAY DIFFRACTION	1.35
7Z58	X-RAY DIFFRACTION	1.35
6EZP	X-RAY DIFFRACTION	1.37
2YJB	X-RAY DIFFRACTION	1.4
8A4W	X-RAY DIFFRACTION	1.4
8UAC	X-RAY DIFFRACTION	1.4
5I4H	X-RAY DIFFRACTION	1.42
5F02	X-RAY DIFFRACTION	1.43
2XU1	X-RAY DIFFRACTION	1.45
6JD8	X-RAY DIFFRACTION	1.46
2VHS	X-RAY DIFFRACTION	1.5
7QKD	X-RAY DIFFRACTION	1.5
2XU5	X-RAY DIFFRACTION	1.6
7Z3T	X-RAY DIFFRACTION	1.6
7ZS7	X-RAY DIFFRACTION	1.6
7ZVF	X-RAY DIFFRACTION	1.6
7ZXA	X-RAY DIFFRACTION	1.6
8QKB	X-RAY DIFFRACTION	1.6
8A4V	X-RAY DIFFRACTION	1.65
7QKC	X-RAY DIFFRACTION	1.69
8AHV	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07711-F1	93.75	0.88

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 (7): 106–107 (cleavage; by autolysis); 107–108 (cleavage; by autolysis); 112–113 (cleavage; by autolysis); 113–114 (cleavage; by autolysis); 138; 276; 300

Ligand- & substrate-binding residues (11): 163; 184; 199; 205; 209; 227; 250; 253; 273; 275; 122

Disulfide bonds (3): 135–178, 169–211, 269–322

Glycosylation sites (1): 221

Mutagenesis-validated functional residues (1):

Position	Phenotype
138	catalytically inactive. unable to autocleave procathepsin l.

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-1236977	Endosomal/Vacuolar pathway
R-HSA-1442490	Collagen degradation
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-2024096	HS-GAG degradation
R-HSA-2132295	MHC class II antigen presentation
R-HSA-8939242	RUNX1 regulates transcription of genes involved in differentiation of keratinocytes
R-HSA-9678110	Attachment and Entry
R-HSA-9694614	Attachment and Entry
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-1643685	Disease
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-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-9678108	SARS-CoV-1 Infection
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9772572	Early SARS-CoV-2 Infection Events
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 389 (showing top): MODULE_172, LEE_SP4_THYMOCYTE, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_SECRETORY_GRANULE, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_MEMBRANE_FUSION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, MODULE_128, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (19): adaptive immune response (GO:0002250), proteolysis (GO:0006508), protein autoprocessing (GO:0016540), fusion of virus membrane with host plasma membrane (GO:0019064), receptor-mediated endocytosis of virus by host cell (GO:0019065), antigen processing and presentation (GO:0019882), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), collagen catabolic process (GO:0030574), zymogen activation (GO:0031638), enkephalin processing (GO:0034230), fusion of virus membrane with host endosome membrane (GO:0039654), CD4-positive, alpha-beta T cell lineage commitment (GO:0043373), symbiont entry into host cell (GO:0046718), antigen processing and presentation of peptide antigen (GO:0048002), obsolete proteolysis involved in protein catabolic process (GO:0051603), elastin catabolic process (GO:0060309), macrophage apoptotic process (GO:0071888), cellular response to thyroid hormone stimulus (GO:0097067), extracellular matrix disassembly (GO:0022617)

GO Molecular Function (10): fibronectin binding (GO:0001968), cysteine-type endopeptidase activity (GO:0004197), collagen binding (GO:0005518), cysteine-type peptidase activity (GO:0008234), histone binding (GO:0042393), proteoglycan binding (GO:0043394), serpin family protein binding (GO:0097655), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (16): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), lysosome (GO:0005764), multivesicular body (GO:0005771), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), extracellular matrix (GO:0031012), endolysosome lumen (GO:0036021), chromaffin granule (GO:0042583), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), endocytic vesicle lumen (GO:0071682), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Extracellular matrix organization	2
Immune System	2
Antigen processing-Cross presentation	1
Degradation of the extracellular matrix	1
Toll-like Receptor Cascades	1
Collagen formation	1
Heparan sulfate/heparin (HS-GAG) metabolism	1
Adaptive Immune System	1
Transcriptional regulation by RUNX1	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1
Regulation of CDH1 Function	1
Activation of STAT3 by cadherin engagement	1
Class I MHC mediated antigen processing & presentation	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
protein processing	2
membrane fusion involved in viral entry into host cell	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
cytoplasm	2
immune response	1
protein metabolic process	1
membrane fusion	1
receptor-mediated endocytosis	1
symbiont entry into host cell	1
endocytosis involved in viral entry into host cell	1
immune system process	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
catabolic process	1
collagen metabolic process	1
peptide hormone processing	1
alpha-beta T cell lineage commitment	1
CD4-positive, alpha-beta T cell differentiation	1
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1
viral life cycle	1
symbiont entry into host	1
antigen processing and presentation	1
glycoprotein catabolic process	1
elastin metabolic process	1
inflammatory cell apoptotic process	1
myeloid cell apoptotic process	1
leukocyte apoptotic process	1
cellular response to hormone stimulus	1
response to thyroid hormone	1
cellular component disassembly	1
extracellular matrix organization	1
endopeptidase activity	1
cysteine-type peptidase activity	1
protein-containing complex binding	1
peptidase activity	1
carbohydrate derivative binding	1
binding	1
hydrolase activity	1

Protein interactions and networks

STRING

3181 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSL	CST7	O76096	913
CTSL	CSTB	P04080	886
CTSL	TMPRSS2	O15393	864
CTSL	LGMN	Q99538	839
CTSL	CTSD	P07339	806
CTSL	ACE2	Q9BYF1	806
CTSL	FURIN	P09958	794
CTSL	CSTA	P01040	768
CTSL	CTRB2	Q6GPI1	708
CTSL	CTRB1	P17538	705
CTSL	BSG	P35613	699
CTSL	LDLR	P01130	678
CTSL	PSAP	P07292	674
CTSL	CTSB	P07858	648
CTSL	SERPINB13	Q9UIV8	623

IntAct

57 interactions, top by confidence:

A	B	Type	Score
CTSV	CTSL	psi-mi:“MI:0915”(physical association)	0.720
CTSV	CTSL	psi-mi:“MI:0914”(association)	0.720
S	CTSL	psi-mi:“MI:0570”(protein cleavage)	0.620
CTSL	S	psi-mi:“MI:0570”(protein cleavage)	0.620
CTSL	SGTA	psi-mi:“MI:0915”(physical association)	0.560
SGTA	CTSL	psi-mi:“MI:0915”(physical association)	0.560
CTSL	srp-6	psi-mi:“MI:0915”(physical association)	0.540
srp-6	CTSL	psi-mi:“MI:0407”(direct interaction)	0.540
CST1	CTSV	psi-mi:“MI:0914”(association)	0.530
CTSK	CTSV	psi-mi:“MI:0914”(association)	0.530
CTSL	CTSH	psi-mi:“MI:0914”(association)	0.530
CST6	CTSV	psi-mi:“MI:0914”(association)	0.530
CST7	CTSL	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
SLC25A6	HRAS	psi-mi:“MI:0914”(association)	0.530
	CTSL	psi-mi:“MI:0570”(protein cleavage)	0.440
RELB	CTSL	psi-mi:“MI:0915”(physical association)	0.370
BTN3A3	CTSL	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (296): SGTA (Two-hybrid), CTSL (Affinity Capture-RNA), CTSL (Affinity Capture-RNA), CLTCL1 (Affinity Capture-MS), CTSL3P (Affinity Capture-MS), CTSH (Affinity Capture-MS), CCDC88A (Affinity Capture-MS), CTSL (Affinity Capture-MS), PGD (Co-fractionation), CTSL3P (Affinity Capture-MS), CTSL (Affinity Capture-MS), CCDC88A (Affinity Capture-MS), CTSL (Affinity Capture-MS), CTSL (Affinity Capture-MS), CTSL (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

6 interactions.

A	Effect	B	Mechanism
aloxistatin	“down-regulates activity”	CTSL	“chemical inhibition”
CTSL	“up-regulates activity”	S	cleavage
CTSL	“down-regulates quantity by destabilization”	BGLAP	cleavage
NSFL1C	“down-regulates activity”	CTSL	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	7	19.5×	1e-05
Post-translational protein phosphorylation	5	16.2×	1e-03
Platelet degranulation	5	14.2×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of proteolysis	5	93.6×	6e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1308 predictions. Top by Δscore:

Variant	Effect	Δscore
9:87728146:CATGG:C	donor_loss	1.0000
9:87728147:ATGGT:A	donor_loss	1.0000
9:87728148:TGGTA:T	donor_loss	1.0000
9:87728149:GGT:G	donor_loss	1.0000
9:87728150:G:GG	donor_gain	1.0000
9:87728150:G:T	donor_loss	1.0000
9:87728151:T:A	donor_loss	1.0000
9:87728232:A:AG	acceptor_gain	1.0000
9:87728245:T:TA	acceptor_gain	1.0000
9:87728248:A:AG	acceptor_gain	1.0000
9:87728249:G:GG	acceptor_gain	1.0000
9:87728249:GACCA:G	acceptor_gain	1.0000
9:87728392:ATCAG:A	donor_loss	1.0000
9:87728393:TCAG:T	donor_loss	1.0000
9:87728394:CAG:C	donor_loss	1.0000
9:87728395:AGGT:A	donor_loss	1.0000
9:87728396:GG:G	donor_loss	1.0000
9:87728397:G:A	donor_loss	1.0000
9:87728583:AG:A	acceptor_gain	1.0000
9:87728584:GG:G	acceptor_gain	1.0000
9:87728810:G:GG	donor_gain	1.0000
9:87729562:A:AG	acceptor_gain	1.0000
9:87729567:T:TA	acceptor_gain	1.0000
9:87729570:A:AG	acceptor_gain	1.0000
9:87729570:AAGGA:A	acceptor_loss	1.0000
9:87729571:A:G	acceptor_gain	1.0000
9:87729571:AGG:A	acceptor_loss	1.0000
9:87729572:G:GC	acceptor_loss	1.0000
9:87729572:GGAA:G	acceptor_gain	1.0000
9:87729732:GAAG:G	donor_gain	1.0000

AlphaMissense

2231 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:87728609:T:C	F141L	0.998
9:87728611:T:A	F141L	0.998
9:87728611:T:G	F141L	0.998
9:87730493:G:C	K299N	0.997
9:87730493:G:T	K299N	0.997
9:87731069:T:A	C322S	0.997
9:87731070:G:C	C322S	0.997
9:87728612:A:C	S142R	0.996
9:87728614:T:A	S142R	0.996
9:87728614:T:G	S142R	0.996
9:87731023:G:C	W306C	0.996
9:87731023:G:T	W306C	0.996
9:87728117:T:C	F73L	0.995
9:87728119:C:A	F73L	0.995
9:87728119:C:G	F73L	0.995
9:87728605:G:C	W139C	0.995
9:87728605:G:T	W139C	0.995
9:87728672:A:C	S162R	0.995
9:87728673:G:T	S162I	0.995
9:87728674:T:A	S162R	0.995
9:87728674:T:G	S162R	0.995
9:87731070:G:A	C322Y	0.995
9:87728396:G:C	Q132H	0.994
9:87728396:G:T	Q132H	0.994
9:87728603:T:A	W139R	0.994
9:87728603:T:C	W139R	0.994
9:87730482:T:A	W296R	0.994
9:87730482:T:C	W296R	0.994
9:87730496:C:A	N300K	0.994
9:87730496:C:G	N300K	0.994

dbSNP variants (sampled 300 via entrez): RS1000652961 (9:87726199 G>C), RS1001064493 (9:87726440 C>G), RS1001584129 (9:87729841 T>A,G), RS1002182287 (9:87731385 T>C), RS1002290595 (9:87725556 T>C), RS1003093881 (9:87726143 A>G), RS1003306961 (9:87726953 G>T), RS1003401605 (9:87727219 C>A,G,T), RS1003880187 (9:87727836 A>G), RS1004307373 (9:87731651 A>G,T), RS1004400738 (9:87731970 A>G), RS1004984804 (9:87726902 C>T), RS1005320865 (9:87730073 A>C), RS1005554386 (9:87730312 G>A), RS1005790661 (9:87726755 G>C)

Disease associations

OMIM: gene MIM:116880 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003542_151	Night sleep phenotypes	5.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111380 (SELECTIVITY GROUP), CHEMBL3837 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 55,706 (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
CHEMBL481611	ODANACATIB	3	804
CHEMBL590799	CAMOSTAT	3	6,733
CHEMBL203665	RELACATIB	2	115
CHEMBL296588	PEPSTATIN	2	26,094
CHEMBL359965	ALLICIN	2	14,806
CHEMBL371064	BALICATIB	2	97
CHEMBL5095230	ATUZAGINSTAT	2	72
CHEMBL63440	ALOXISTATIN	2	723
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 (13 total), top 13:

Ligand	Action	Affinity	Parameter
AC1115	Inhibition	10.22	pIC50
MG-101	Inhibition	10.19	pKi
VBY-825	Inhibition	9.6	pKi
D6-3	Inhibition	9.57	pIC50
CAA0225	Inhibition	8.7	pIC50
GC-376	Inhibition	8.36	pIC50
LHVS	Inhibition	8.15	pIC50
compound 1 [PMID: 40415551]	Inhibition	7.54	pIC50
K11777	Inhibition	7.3	pKi
KGP94	Inhibition	6.9	pIC50
Mpro inhibitor 13b	Inhibition	6.53	pKi
compound 4d [PMID: 38746883]	Inhibition	6.15	pIC50
UAWJ9-36-3	Inhibition	5.74	pIC50

Binding affinities (BindingDB)

586 measured of 937 human assays (1139 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
(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
(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)-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)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(2-methyl-4-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.505 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[3-(5-bromo-3-fluoro-2-pyridinyl)-1-methylazetidine-3-carbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.525 nM	US-8822505: Azetidine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.543 nM	US-9409882: Pyridine derivatives
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
(2S,4R)-N-(1-cyanocyclopropyl)-1-[1-(3-fluoro-5-iodo-2-pyridinyl)cyclopropanecarbonyl]-4-(2-fluorophenyl)sulfonylpyrrolidine-2-carboxamide	IC50	0.6 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(4-chloro-2-fluorophenyl)cyclopropanecarbonyl]-4-(2-chloro-4-fluorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.602 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-(2-chloro-4-methoxyphenyl)sulfonyl-1-[1-(5-chloro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.606 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.618 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-trifluoroethoxy)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.675 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3-fluoro-5-iodo-2-pyridinyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.678 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-[2-chloro-4-(2-chloro-4-pyridinyl)phenyl]sulfonyl-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.686 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[3-(5-chloro-2-pyridinyl)-1-(2,2-difluoroethyl)azetidine-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoroethoxy)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.694 nM	US-8822505: Azetidine derivatives
(2S,4R)-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.696 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)-4-(2-fluorophenyl)sulfonylpyrrolidine-2-carboxamide	IC50	0.7 nM	US-9409882: Pyridine derivatives
(2S,4R)-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3,5-dichloro-2-pyridinyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.703 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[3-(5-bromo-3-fluoro-2-pyridinyl)-1-ethylazetidine-3-carbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.721 nM	US-8822505: Azetidine derivatives
(2S,4R)-1-[1-(5-bromo-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chloro-4-methoxyphenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.734 nM	US-9409882: Pyridine derivatives
2-cyano-4-(cyclohexylamino)-N-{2-[4-(pyrrolidin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.75 nM
(2S,4R)-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.768 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)-4-[3-(4-fluorophenyl)phenyl]sulfonylpyrrolidine-2-carboxamide	IC50	0.77 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[3-(5-bromo-2-pyridinyl)-1-(2,2-difluoroethyl)azetidine-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoroethoxy)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.779 nM	US-8822505: Azetidine derivatives
(2S,4R)-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3,5-dichloro-2-pyridinyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.779 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[2-(5-chloro-3-fluoro-2-pyridinyl)azetidine-2-carbonyl]-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.791 nM	US-8822505: Azetidine derivatives
(2S,4R)-1-[1-(5-chloro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(2,2,2-trifluoroethoxy)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.825 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[3-(5-bromo-3-fluoro-2-pyridinyl)-1-formylazetidine-3-carbonyl]-4-[2-chloro-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxyphenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.9 nM	US-8822505: Azetidine derivatives
tert-butyl 2-(5-chloro-3-fluoro-2-pyridinyl)-2-[(2S,4R)-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-2-[(1-cyanocyclopropyl)carbamoyl]pyrrolidine-1-carbonyl]azetidine-1-carboxylate	IC50	0.965 nM	US-8822505: Azetidine derivatives
(2S,4R)-1-[3-(5-bromo-3-fluoro-2-pyridinyl)-1-(2,2-difluoroethyl)azetidine-3-carbonyl]-4-[2-chloro-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxyphenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	1 nM	US-8822505: Azetidine derivatives

ChEMBL bioactivities

2023 potent at pChembl≥5 of 2286 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.60	Ki	0.025	nM	CHEMBL190121
10.44	Ki	0.036	nM	CHEMBL191558
10.40	Ki	0.04	nM	CHEMBL202668
10.35	Ki	0.045	nM	CHEMBL1651355
10.31	Ki	0.049	nM	CHEMBL286722
10.19	Ki	0.0645	nM	CHEMBL304784
10.17	Ki	0.068	nM	RELACATIB
10.03	IC50	0.094	nM	CHEMBL4441303
10.00	IC50	0.1	nM	CHEMBL31788
10.00	IC50	0.1	nM	CHEMBL287630
9.90	Ki	0.1259	nM	CHEMBL4212454
9.82	IC50	0.15	nM	MG-132
9.80	Ki	0.16	nM	CHEMBL604281
9.77	IC50	0.17	nM	CHEMBL218024
9.70	IC50	0.2	nM	K-777
9.66	Ki	0.22	nM	CHEMBL1651361
9.60	Ki	0.2512	nM	CHEMBL4755248
9.60	IC50	0.25	nM	CHEMBL3427166
9.52	IC50	0.3	nM	CHEMBL6083070
9.51	IC50	0.31	nM	CHEMBL385632
9.48	IC50	0.33	nM	CHEMBL374890
9.48	IC50	0.3311	nM	CHEMBL6190904
9.47	IC50	0.34	nM	CHEMBL220496
9.44	IC50	0.36	nM	CHEMBL6091804
9.44	Ki	0.36	nM	CHEMBL1651353
9.41	Ki	0.39	nM	CHEMBL1651354
9.40	Ki	0.4	nM	CHEMBL4078345
9.40	Ki	0.4	nM	CHEMBL1651352
9.39	IC50	0.41	nM	CHEMBL6078112
9.37	Ki	0.43	nM	CHEMBL194643
9.36	IC50	0.437	nM	CHEMBL492175
9.35	IC50	0.45	nM	CHEMBL219536
9.33	Ki	0.47	nM	CHEMBL177914
9.31	Ki	0.49	nM	CHEMBL284939
9.30	Ki	0.5012	nM	CHEMBL4746022
9.30	Ki	0.5012	nM	CHEMBL4217414
9.30	IC50	0.5	nM	CHEMBL6083027
9.28	IC50	0.52	nM	CHEMBL218007
9.28	IC50	0.53	nM	CHEMBL1807649
9.24	Ki	0.57	nM	CHEMBL194861
9.24	IC50	0.58	nM	CHEMBL436303
9.22	Ki	0.6	nM	CHEMBL48837
9.22	Ki	0.6	nM	CHEMBL4584291
9.21	Ki	0.61	nM	CHEMBL4083754
9.20	Ki	0.63	nM	CHEMBL205172
9.20	IC50	0.632	nM	CHEMBL4447348
9.20	Ki	0.631	nM	CHEMBL4744431
9.19	Ki	0.64	nM	CHEMBL132586
9.17	IC50	0.68	nM	CHEMBL384685
9.17	IC50	0.68	nM	K-777

PubChem BioAssay actives

2015 with measured affinity, of 3976 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)-1-cyclohexylpropan-2-yl] N-[cyano(methyl)amino]carbamate	238799: Inhibition constant against human cathepsin L using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-phenylbutan-2-yl] N-[cyano(methyl)amino]carbamate	238813: Inhibition constant against human cathepsin L using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-phenylurea	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	<0.0001	uM
benzyl N-[(2S)-3-methyl-1-oxo-1-[[(2S)-1-oxo-3-phenylpropan-2-yl]amino]butan-2-yl]carbamate	2105686: Inhibition of Cathepsin L (unknown origin) assessed as inhibition constant using Z-RR-AMC as fluorogenic substrate by fluorescence based microplate analysis	ki	<0.0001	uM
benzyl N-[(2S)-1-[[(2S,3R)-2-(benzenesulfonyl)-4-oxoazetidin-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	51218: Inhibition of recombinant human Cathepsin L	ic50	0.0001	uM
benzyl N-[(2S)-1-oxo-1-[[(3R,4S)-2-oxo-4-phenylsulfanylazetidin-3-yl]amino]-3-phenylpropan-2-yl]carbamate	51218: Inhibition of recombinant human Cathepsin L	ic50	0.0001	uM
3-tert-butyl-N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-1-oxo-3-phenylpropan-2-yl]-1-methylpyrazole-5-carboxamide	1698844: Inhibition of human cathepsin L using Z-Phe-Arg-7-amido-4-methylcoumarin as substrate preincubated for 2 mins followed by substrate addition by fluorimetric assay	ki	0.0001	uM
[(2S)-1-[[(2S)-1-[[(E,2S)-5-[(2S)-3-methoxy-2-(2-methylpropyl)-5-oxo-2H-pyrrol-1-yl]-5-oxo-1-phenylpent-3-en-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl] (2S,3S)-2-(dimethylamino)-3-methylpentanoate	1526361: Inhibition of human cathepsin L using fluorogenic substrate cbz-FR-AMC monitored for 90 to 120 mins by spectrophotometry	ic50	0.0001	uM
(2S)-2-acetamido-4-methyl-N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxohexan-2-yl]amino]pentan-2-yl]pentanamide	2105686: Inhibition of Cathepsin L (unknown origin) assessed as inhibition constant using Z-RR-AMC as fluorogenic substrate by fluorescence based microplate analysis	ki	0.0001	uM
benzyl N-[(2S)-4-methyl-1-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]carbamate	1922129: Inhibition of Cathepsin L (unknown origin) preincubated for 30 mins followed by fluorogenic substrate addition and measured for 15 mins by fluorescence microplate reader analysis	ic50	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
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	0.0002	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-1-oxo-3-phenylpropan-2-yl]carbamate	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0002	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	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0002	uM
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]-4-methylpiperazine-1-carboxamide	1561237: Inhibition of human Cathepsin L using Cbz-Phe-Arg-AMC as substrate by fluorescence assay	ic50	0.0002	uM
sodium (2S)-1-hydroxy-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate	1871201: Inhibition of human cathepsin L	ic50	0.0003	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	0.0003	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	0.0003	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	0.0003	uM
(2S)-2-[(3-bromophenyl)sulfonylamino]-3-(3-chlorophenyl)-N-[(1R,2R)-1-cyano-2-phenylmethoxypropyl]propanamide	1683750: Inhibition of human cathepsin L	ki	0.0003	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	609674: Inhibition of human recombinant cathepsin L using Z-LR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-naphthalen-2-yl-1-oxo-1-[[(4S)-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]propan-2-yl]naphthalene-1-carboxamide	255214: Apparent inhibitory constant against human cathepsin L	ki	0.0004	uM
benzyl N-[(2S)-1-oxo-1-[[(E,3S)-6-oxo-1-phenylhept-4-en-3-yl]amino]-3-phenylpropan-2-yl]carbamate	1458683: Inhibition of human cathepsin L using Cbz-Phe-Arg-AMC as substrate after 10 mins by fluorescence assay	ki	0.0004	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	0.0004	uM
3-acetyl-8-chloro-2-(4-chloroanilino)-6-nitro-1H-quinolin-4-one	350738: Inhibition of human liver cathepsin L after 30 mins by fluorometric end-point assay	ic50	0.0004	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-3-cyclohexyl-1-oxopropan-2-yl]carbamate	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0004	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamate	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0004	uM
1-benzyl-3-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]urea	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0004	uM
benzyl N-[(2S)-1-[[(2S)-1-(4-hydroxyphenyl)-3-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	255214: Apparent inhibitory constant against human cathepsin L	ki	0.0005	uM
3-tert-butyl-N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-1-methylpyrazole-5-carboxamide	1698844: Inhibition of human cathepsin L using Z-Phe-Arg-7-amido-4-methylcoumarin as substrate preincubated for 2 mins followed by substrate addition by fluorimetric assay	ki	0.0005	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	0.0005	uM
N-[(2S)-3-(3-bromophenyl)-1-[[(1R,2R)-1-cyano-2-phenylmethoxypropyl]amino]-1-oxopropan-2-yl]-3-tert-butyl-1-methylpyrazole-5-carboxamide	1683750: Inhibition of human cathepsin L	ki	0.0005	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	219375: Inhibitory activity against Human cathepsin L	ki	0.0005	uM
N-[(2S)-4-methyl-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]furan-2-carboxamide	609674: Inhibition of human recombinant cathepsin L using Z-LR-AMC as substrate by fluorescence assay	ic50	0.0005	uM
benzyl N-[(2S)-1-[[(2S)-1-(4-butoxyphenyl)-3,4-dioxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	51355: Ability to block cathepsin L-catalyzed hydrolysis of the fluorogenic substrate Z-Phe-Arg-NHMec	ki	0.0006	uM
N-[(2S)-3-naphthalen-2-yl-1-oxo-1-[[(4S)-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]propan-2-yl]-1-benzofuran-2-carboxamide	255214: Apparent inhibitory constant against human cathepsin L	ki	0.0006	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	0.0006	uM
benzyl N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate	1458683: Inhibition of human cathepsin L using Cbz-Phe-Arg-AMC as substrate after 10 mins by fluorescence assay	ki	0.0006	uM
[(2S)-1-[[(2S)-1-[[(E,2S)-5-[(2S)-3-methoxy-2-(2-methylpropyl)-5-oxo-2H-pyrrol-1-yl]-5-oxo-1-phenylpent-3-en-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl] (2S)-2-(dimethylamino)-3-methylbutanoate	1526361: Inhibition of human cathepsin L using fluorogenic substrate cbz-FR-AMC monitored for 90 to 120 mins by spectrophotometry	ic50	0.0006	uM
4-chloro-N-[(2S)-1-oxo-1-[[(E,3S)-6-oxo-1-phenylhept-4-en-3-yl]amino]-3-phenylpropan-2-yl]benzamide	1541383: Inhibition of human Cathepsin L assessed as inhibition constant using Cbz-Phe-Arg-AMC as substrate by fluorescence assay	ki	0.0006	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	0.0006	uM
3-bromo-N-[(2S)-3-(3-chlorophenyl)-1-[[(1R,2R)-1-cyano-2-phenylmethoxypropyl]amino]-1-oxopropan-2-yl]benzamide	1683750: Inhibition of human cathepsin L	ki	0.0006	uM
benzyl N-[1-[[1,2-dioxo-1-(pyridin-2-ylmethylamino)hexan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate	2105686: Inhibition of Cathepsin L (unknown origin) assessed as inhibition constant using Z-RR-AMC as fluorogenic substrate by fluorescence based microplate analysis	ki	0.0006	uM
N’-(5-bromo-2-cyanopyrimidin-4-yl)-4-[(4-methylpiperazin-1-yl)methyl]-N’-(2-methylpropyl)benzohydrazide	1391660: Inhibition of human cathepsin L	ic50	0.0007	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	0.0007	uM
benzyl N-[1-oxo-1-[(1-oxo-3-phenylpropan-2-yl)amino]-3-phenylpropan-2-yl]carbamate	219373: Inhibitory activity against cathepsin L, lysosomal cysteine protease	ic50	0.0007	uM
(2S)-3-methyl-N-[(2S)-3-methyl-1-oxobutan-2-yl]-2-(naphthalen-1-ylsulfonylamino)pentanamide	51350: Inhibition of human cathepsin L.	ic50	0.0007	uM
[(2S)-1-cyclohexylpropan-2-yl] 1-cyanoazetidine-2-carboxylate	241928: Inhibitory concentration against human cathepsin L using 5 uM Cbz-Phe-Arg-AMC	ic50	0.0007	uM
(2S)-1-hydroxy-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid	1983343: Inhibition of human Cathepsin L using HiLyte Fluor488TM as substrate pre-incubated for 60 mins in presence of GSH followed by substrate addition measured after 30 mins by fluorescence based assay	ic50	0.0007	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	7
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	7
bisphenol A	affects expression, decreases expression, increases expression	4
Cyclosporine	increases expression, decreases activity	4
Air Pollutants	decreases expression, increases abundance, increases expression, affects cotreatment	3
Tobacco Smoke Pollution	increases expression	3
Cadmium Chloride	increases expression, decreases reaction, increases cleavage, increases abundance, increases palmitoylation	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
nickel sulfate	decreases expression, increases expression	2
Decitabine	affects expression, increases expression	2
Arsenic Trioxide	increases abundance, affects expression, affects binding, decreases reaction, affects response to substance	2
Cisplatin	affects expression, decreases response to substance	2
Ivermectin	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
Paclitaxel	increases response to substance, decreases response to substance	2
tert-Butylhydroperoxide	increases expression, decreases expression	2
GSK-J4	increases expression	1
GSK2795039	affects reaction, decreases cleavage	1
TAK-243	increases sumoylation	1
sotorasib	affects cotreatment, decreases expression	1
tannic acid	decreases expression	1
dicrotophos	decreases expression	1
beta-N-methylamino-L-alanine	increases activity, affects cotreatment	1
2,4,6-tribromophenol	decreases expression	1
2,4-diaminobutyric acid	affects cotreatment, increases activity	1
lead acetate	increases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
asperphenamate	affects binding, decreases activity	1

ChEMBL screening assays

521 unique, capped per target: 494 binding, 11 admet, 8 toxicity, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5106296	Binding	Selectivity ratio of IC50 for Cathepsin L (unknown origin) to IC50 for Cathepsin K (unknown origin)	Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis. — Bioorg Med Chem Lett
CHEMBL4322235	ADMET	Inhibition of human cathepsin L assessed as ratio of Kcat/Km using Z-Phe-Arg-MCA as substrate by spectrofluorometric method	Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity? — J Med Chem
CHEMBL5154227	Toxicity	Inhibition of human cathepsin L using Z-Leu-Arg-AMC as substrate by FRET assay	Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2VF	Abcam HEK293T CTSL KO	Transformed cell line	Female
CVCL_D7N5	Ubigene A-549 CTSL KO	Cancer cell line	Male

Clinical trials (associated diseases)

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