HPN

Summary

HPN (hepsin, HGNC:5155) is a protein-coding gene on chromosome 19q13.11, encoding Serine protease hepsin (P05981). Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL.

This gene encodes a type II transmembrane serine protease that may be involved in diverse cellular functions, including blood coagulation and the maintenance of cell morphology. Expression of the encoded protein is associated with the growth and progression of cancers, particularly prostate cancer. The protein is cleaved into a catalytic serine protease chain and a non-catalytic scavenger receptor cysteine-rich chain, which associate via a single disulfide bond. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 3249 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 72 total
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001384133

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5155
Approved symbol	HPN
Name	hepsin
Location	19q13.11
Locus type	gene with protein product
Status	Approved
Aliases	TMPRSS1
Ensembl gene	ENSG00000105707
Ensembl biotype	protein_coding
OMIM	142440
Entrez	3249

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 49 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000262626, ENST00000392226, ENST00000541345, ENST00000593305, ENST00000596662, ENST00000597419, ENST00000599363, ENST00000600390, ENST00000600675, ENST00000672452, ENST00000673426, ENST00000863190, ENST00000863191, ENST00000863192, ENST00000863193, ENST00000863194, ENST00000863195, ENST00000863196, ENST00000863197, ENST00000863198, ENST00000863199, ENST00000863200, ENST00000863201, ENST00000863202, ENST00000863203, ENST00000863204, ENST00000863205, ENST00000863206, ENST00000863207, ENST00000863208, ENST00000863209, ENST00000863210, ENST00000863211, ENST00000863212, ENST00000863213, ENST00000863214, ENST00000863215, ENST00000863216, ENST00000863217, ENST00000863218, ENST00000863219, ENST00000863220, ENST00000863221, ENST00000863222, ENST00000863223, ENST00000863224, ENST00000863225, ENST00000863226, ENST00000863227, ENST00000922334, ENST00000922335, ENST00000922336, ENST00000952471, ENST00000952472

RefSeq mRNA: 4 — MANE Select: NM_001384133 NM_001375441, NM_001384133, NM_002151, NM_182983

CCDS: CCDS32993

Canonical transcript exons

ENST00000672452 — 13 exons

Exon	Start	End
ENSE00000953257	35049290	35049391
ENSE00001253074	35065868	35066032
ENSE00003479443	35060129	35060169
ENSE00003480079	35049475	35049516
ENSE00003491113	35060627	35060817
ENSE00003511777	35059874	35059996
ENSE00003515280	35065539	35065681
ENSE00003523512	35060347	35060512
ENSE00003552239	35059673	35059802
ENSE00003579991	35065250	35065345
ENSE00003631559	35042453	35042522
ENSE00003910460	35041721	35041872
ENSE00003911265	35066249	35066573

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 99.50.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7960 / max 897.0569, expressed in 408 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175197	4.5222	330
175198	0.0936	53
175196	0.0810	33
175199	0.0555	30
208778	0.0437	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.50	gold quality
body of pancreas	UBERON:0001150	98.77	gold quality
metanephros cortex	UBERON:0010533	97.72	gold quality
liver	UBERON:0002107	97.46	gold quality
adult mammalian kidney	UBERON:0000082	96.09	gold quality
kidney	UBERON:0002113	89.94	gold quality
pancreas	UBERON:0001264	89.22	gold quality
nephron tubule	UBERON:0001231	88.90	gold quality
cortex of kidney	UBERON:0001225	88.66	gold quality
body of stomach	UBERON:0001161	88.09	gold quality
gastrocnemius	UBERON:0001388	86.34	gold quality
left lobe of thyroid gland	UBERON:0001120	86.31	gold quality
kidney epithelium	UBERON:0004819	86.10	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.04	gold quality
stomach	UBERON:0000945	84.72	gold quality
right lobe of thyroid gland	UBERON:0001119	84.57	gold quality
thyroid gland	UBERON:0002046	84.39	gold quality
muscle of leg	UBERON:0001383	84.17	gold quality
pancreatic ductal cell	CL:0002079	84.01	silver quality
metanephric glomerulus	UBERON:0004736	82.90	gold quality
metanephros	UBERON:0000081	82.89	gold quality
adenohypophysis	UBERON:0002196	82.72	gold quality
upper lobe of left lung	UBERON:0008952	82.29	gold quality
renal glomerulus	UBERON:0000074	82.10	gold quality
upper lobe of lung	UBERON:0008948	81.39	gold quality
apex of heart	UBERON:0002098	81.22	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.84	gold quality
pituitary gland	UBERON:0000007	80.26	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	27.08
E-CURD-112	no	3.28
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPG, NR3C1, SP1, TCF3, TFAP2A

miRNA regulators (miRDB)

28 targeting HPN, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-4535	97.27	65.17	469
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-6775-3P	95.76	65.91	982
HSA-MIR-4508	90.37	59.62	240
HSA-MIR-4707-3P	86.55	62.02	99

Literature-anchored findings (GeneRIF, showing 35)

• Hepsin and maspin are inversely expressed in laser capture microdissectioned prostate cancer (PMID:12629351)
• Hepsin is functionally linked to hepatocyte growth factor/MET pathway, which may contribute to prostate cancer progression. (PMID:15792801)
• A major 11-locus haplotype is significantly associated with prostate cancer, which provides further support that HPN is a potentially important candidate gene involved in prostate cancer susceptibility. (PMID:16783571)
• the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression (PMID:16908524)
• Our findings suggest that the balance between hepsin and its inhibitor, HAI-2, may have prognostic value in RCC. (PMID:17309599)
• We analyzed all the common variations using tag SNP in the HPN and LTBP4 genes for association with IA in 390 patients and 642 controls in the Dutch population. (PMID:18487557)
• Hepsin showed potential inhibitory effects mediated by the induction of 14-3-3sigma expression which leads to both cell cycle arrest at the G2/M phase (PMID:18698500)
• Ln-332 may be one mechanism by which hepsin promotes prostate tumor progression and metastasis, possibly by up-regulating prostate cancer cell motility. (PMID:18784072)
• Hepsin activates prostasin and cleaves the extracellular domain of the epidermal growth factor receptor. (PMID:19911255)
• HGF is activated by the transmembrane serine proteases matriptase and hepsin, but not by the membrane-associated protease uPA. (PMID:20015050)
• Germline genetic variation of HPN does not seem to contribute to risk of prostate cancer or prognosis. (PMID:20166135)
• Hepsin activity was inhibited by anthralin and increased by resveratrol. (PMID:20673210)
• hepsin expression is frequently up-regulated in breast cancer tissues, which is associated with tumor growth and progression (PMID:21383634)
• Elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. (PMID:21750652)
• These findings suggest that the MSP/RON signaling pathway may be regulated by hepsin in tissue homeostasis and in disease pathologies, such as in cancer and immune disorders. (PMID:21875933)
• The results of this study suggest that, in Korean men, some polymorphisms in the HPN gene might be associated with the risk of developing prostate cancer. (PMID:22665141)
• Hepsin suppressed CDK11p58 internal ribosome entry site activity in prostate cancer cells by modulating UNR expression and eIF-2alpha phosphorylation. (PMID:25576733)
• Low expression levels of hepsin and TMPRSS3 are associated with poor breast cancer survival (PMID:26014348)
• The Hepsin pathway acts in concert with Wnt pathway to promote prostate cancer progression. (PMID:26139199)
• The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion (PMID:26165838)
• These data demonstrate that the membrane-bound serine protease hepsin is the enzyme responsible for the physiological cleavage of uromodulin. (PMID:26673890)
• significant negative association was found between hepsin expression in endometrial carcinoma cases regarding the grade and the size of tumors as well as myometrial invasion (PMID:26990747)
• Study showed was that Hepsin was downregulated in 78% of gastric cancer. Its high expression seems to predict poor prognosis. These results predicted that hepsin protein expression was one of the significant and independent prognostic factors for overall survival of Gastric Cancer. (PMID:27841306)
• Genetic variation in/near the gene encoding for hepsin protein may influence risk of bipolar disorder and (at least for the rs62122114-A allele) may have functional impact (i.e. differential expression) as evidenced by serum HPN protein expression. (PMID:28886448)
• Data indicate a critical cathepsin D (CtsD)-hepsin signaling in migration and metastasis, which may contribute to understanding of the function and molecular mechanism in breast cancer progression. (PMID:30227221)
• Autoactivation and calpain-1-mediated shedding of hepsin in human hepatoma cells. (PMID:31395734)
• Our results demonstrate that a precise control of Hepsin proteolytic activity is critical for PCa cell fate and suggest, that the interference with ERAD could be a promising therapeutic option, leading to induction of proteotoxicity in hepsin-overexpressing tumors. (PMID:31399560)
• Hepsin: a multifunctional transmembrane serine protease in pathobiology. (PMID:33300264)
• Oncogenic Ras Disrupts Epithelial Integrity by Activating the Transmembrane Serine Protease Hepsin. (PMID:33461973)
• The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING. (PMID:34131022)
• The POR rs10954732 polymorphism decreases susceptibility to hepatocellular carcinoma and hepsin as a prognostic biomarker correlated with immune infiltration based on proteomics. (PMID:35164791)
• Silencing of hepsin and inosine 5-monophosphate dehydrogenase 2 by siRNA reduces prostate cancer cells proliferation. (PMID:35484884)
• Spatial position is a key determinant of N-glycan functionality of the scavenger receptor cysteine-rich domain of human hepsin. (PMID:36802168)
• N-glycosylation mediated folding and quality control in serine proteases of the hepsin family. (PMID:37013685)
• Hepsin promotes breast tumor growth signaling via the TGFbeta-EGFR axis. (PMID:37872868)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	hpn	ENSDARG00000027609
danio_rerio	tmprss12	ENSDARG00000093100
mus_musculus	Hpn	ENSMUSG00000001249
rattus_norvegicus	Hpn	ENSRNOG00000021097
drosophila_melanogaster	Sb	FBGN0003319
drosophila_melanogaster	CG17242	FBGN0250841

Paralogs (17): PRSS22 (ENSG00000005001), PRSS21 (ENSG00000007038), TMPRSS11E (ENSG00000087128), TMPRSS13 (ENSG00000137747), ST14 (ENSG00000149418), TMPRSS11D (ENSG00000153802), TMPRSS15 (ENSG00000154646), TMPRSS3 (ENSG00000160183), TMPRSS5 (ENSG00000166682), TMPRSS7 (ENSG00000176040), TMPRSS9 (ENSG00000178297), TMPRSS2 (ENSG00000184012), TMPRSS11B (ENSG00000185873), TMPRSS6 (ENSG00000187045), TMPRSS11A (ENSG00000187054), TMPRSS11F (ENSG00000198092), PRSS41 (ENSG00000215148)

Protein

Protein identifiers

Serine protease hepsin — P05981 (reviewed: P05981)

Alternative names: Transmembrane protease serine 1

All UniProt accessions (4): A0A140VJK9, P05981, M0QZ63, M0R244

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL. Plays a role in cell growth and maintenance of cell morphology. Plays a role in the proteolytic processing of ACE2. Mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Detected in liver and kidney.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (4): NP_001362370, NP_001371062, NP_002142, NP_892028 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR015352	Hepsin-SRCR_dom	Domain
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00089, PF09272

Enzyme classification (BRENDA):

• EC 3.4.21.106 — hepsin (BRENDA: 6 organisms, 79 substrates, 90 inhibitors, 17 Km, 15 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ABZ-KQSRKFVPY(3-NO2)	0.114	1
ABZ-RAARVVGGY(3-NO2)	0.22	1
ABZ-RKRRGSRGY(3-NO2)	0.189	1
ABZ-RLARVVGGY(3-NO2)	0.29	1
ABZ-RQARAVGGY(3-NO2)	0.191	1
ABZ-RQARVVGGY(3-NO2)	0.369	1
ABZ-RQARYVGGY(3-NO2)	0.175	1
ABZ-RQLRVVGGY(3-NO2)	0.068	1
ABZ-RQRRALEKY(3-NO2)	0.085	1
ABZ-RQRRVVGGY(3-NO2)	0.07	1
ABZ-RQYRVVGGY(3-NO2)	0.109	1
ABZ-RRARVVGGY(3-NO2)	0.072	1
ABZ-SKGRSLIGY(3-NO2)	0.373	1
ABZ-SKLRVVGGY(3-NO2)	0.14	1
L-ASP-L-ALA-L-ALA-L-ARG-4-NITROANILIDE	0.05	1

UniProt features (57 total): strand 21, helix 11, disulfide bond 8, turn 6, active site 3, chain 2, topological domain 2, domain 2, glycosylation site 1, transmembrane region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1Z8G	X-RAY DIFFRACTION	1.55
1O5E	X-RAY DIFFRACTION	1.75
1P57	X-RAY DIFFRACTION	1.75
1O5F	X-RAY DIFFRACTION	1.78
5CE1	X-RAY DIFFRACTION	2.5
3T2N	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05981-F1	91.43	0.83

Antibody-complex structures (SAbDab): 1 — 3T2N

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): 203 (charge relay system); 257 (charge relay system); 353 (charge relay system)

Disulfide bonds (8): 77–140, 90–150, 119–138, 153–277, 188–204, 291–359, 322–338, 349–381

Glycosylation sites (1): 112

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6806942	MET Receptor Activation
R-HSA-8852405	Signaling by MST1

MSigDB gene sets: 291 (showing top): MODULE_172, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, SWEET_KRAS_ONCOGENIC_SIGNATURE, GNF2_GSTM1, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_HOST_MEDIATED_ACTIVATION_OF_VIRAL_TRANSCRIPTION, MODULE_64

GO Biological Process (19): proteolysis (GO:0006508), regulation of cell shape (GO:0008360), positive regulation of gene expression (GO:0010628), negative regulation of epithelial to mesenchymal transition (GO:0010719), positive regulation of plasminogen activation (GO:0010756), protein processing (GO:0016485), positive regulation of cell growth (GO:0030307), basement membrane disassembly (GO:0034769), negative regulation of apoptotic process (GO:0043066), host-mediated activation of viral transcription (GO:0043923), negative regulation of epithelial cell proliferation (GO:0050680), detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), potassium ion transmembrane transport (GO:0071805), cochlea morphogenesis (GO:0090103), response to thyroid hormone (GO:0097066), pilomotor reflex (GO:0097195), positive regulation of hepatocyte proliferation (GO:2000347), positive regulation of thyroid hormone generation (GO:2000611), regulation of biological quality (GO:0065008)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), serine-type exopeptidase activity (GO:0070008), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), cell surface (GO:0009986), membrane (GO:0016020), apical plasma membrane (GO:0016324), neuronal cell body (GO:0043025), extracellular exosome (GO:0070062), nuclear membrane (GO:0031965)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by MET	1
Signaling by Receptor Tyrosine Kinases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
serine-type peptidase activity	2
organelle membrane	2
cellular anatomical structure	2
protein metabolic process	1
regulation of cell morphogenesis	1
regulation of biological quality	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
regulation of plasminogen activation	1
positive regulation of protein processing	1
plasminogen activation	1
proteolysis	1
protein maturation	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
extracellular matrix disassembly	1
basement membrane organization	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
host-mediated perturbation of viral transcription	1
host-mediated activation of viral process	1
negative regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
sensory perception of sound	1
nervous system process	1
detection of mechanical stimulus involved in sensory perception	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cochlea development	1

Protein interactions and networks

STRING

1077 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPN	SPINT1	O43278	814
HPN	AMACR	Q9UHK6	749
HPN	SPINT2	O43291	647
HPN	FOLH1	Q04609	623
HPN	GALNT3	Q14435	528
HPN	MSMB	P08118	500
HPN	SERPINB12	Q96P63	494
HPN	PIM1	P11309	492
HPN	SLC45A3	Q96JT2	489
HPN	F3	P13726	476
HPN	SERPINB5	P36952	461
HPN	LMTK2	Q8IWU2	451
HPN	ETV1	P50549	449
HPN	PCSK7	Q16549	446
HPN	ACE2	Q9BYF1	444

IntAct

19 interactions, top by confidence:

A	B	Type	Score
HPN	BNIP3	psi-mi:“MI:0915”(physical association)	0.560
HPN	SFTPC	psi-mi:“MI:0915”(physical association)	0.560
UPK2	HPN	psi-mi:“MI:0915”(physical association)	0.560
GLP1R	HPN	psi-mi:“MI:0915”(physical association)	0.540
HPN	GLP1R	psi-mi:“MI:0915”(physical association)	0.540
GLP1R	HPN	psi-mi:“MI:0403”(colocalization)	0.540
GPS1	PXDNL	psi-mi:“MI:0914”(association)	0.530
HPN	TOR1A	psi-mi:“MI:0914”(association)	0.350
ADH1A	ADH1B	psi-mi:“MI:0914”(association)	0.350
ATG16L1	HPN	psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350
BNIP3	HPN	psi-mi:“MI:0915”(physical association)	0.000
SFTPC	HPN	psi-mi:“MI:0915”(physical association)	0.000
UPK2	HPN	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (97): EGFR (Biochemical Activity), HPN (Affinity Capture-RNA), UPK2 (Two-hybrid), SFTPC (Two-hybrid), BNIP3 (Two-hybrid), HPN (Affinity Capture-MS), FZD3 (Affinity Capture-MS), GPC6 (Affinity Capture-MS), FNDC3A (Affinity Capture-MS), GLB1L2 (Affinity Capture-MS), SCARB1 (Affinity Capture-MS), PCOLCE2 (Affinity Capture-MS), FAM69A (Affinity Capture-MS), POGLUT1 (Affinity Capture-MS), GALNT7 (Affinity Capture-MS)

ESM2 similar proteins: A0JNK3, A2RT60, A4IHA1, A6YFB5, A9JRB3, B3LVG7, D3ZA76, D3ZKF5, E1BJW1, F1N152, O09127, O13146, O19045, O43464, O88917, O94910, O97831, P00743, P05981, P09958, P23188, P23377, P29122, P29317, P29322, P54753, P54754, P54760, P54761, P56677, P83105, P83110, P98139, Q03145, Q05511, Q06805, Q0IIH7, Q1KL86, Q28193, Q28661

Diamond homologs: A0A126GUP6, A0A182C2Z2, A0A1S4H5M5, A8JUP7, B5U2W0, B7YZU2, F5HKX0, O15393, O35453, O60235, O60259, O97366, P00774, P03951, P03952, P05049, P05981, P08419, P09871, P10323, P13582, P14272, P21902, P23578, P25155, P26262, P28175, P29293, P31394, P33587, P35035, P35036, P35037, P35039, P35041, P35045, P35046, P35047, P40313, P48038

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HPN	“up-regulates activity”	F7	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2104 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35060103:T:TA	acceptor_gain	1.0000
19:35060112:A:AG	acceptor_gain	1.0000
19:35060510:GGA:G	donor_gain	1.0000
19:35060511:GA:G	donor_gain	1.0000
19:35060511:GAG:G	donor_gain	1.0000
19:35060513:G:GG	donor_gain	1.0000
19:35065245:CACA:C	acceptor_loss	1.0000
19:35065248:A:AG	acceptor_gain	1.0000
19:35065249:G:GA	acceptor_gain	1.0000
19:35065249:GA:G	acceptor_gain	1.0000
19:35065249:GAA:G	acceptor_gain	1.0000
19:35065249:GAAT:G	acceptor_gain	1.0000
19:35065249:GAATA:G	acceptor_gain	1.0000
19:35065346:G:GA	donor_loss	1.0000
19:35065346:G:GG	donor_gain	1.0000
19:35065347:T:G	donor_loss	1.0000
19:35065680:AGGTG:A	donor_loss	1.0000
19:35065682:G:GA	donor_loss	1.0000
19:35065683:T:A	donor_loss	1.0000
19:35065864:CCA:C	acceptor_loss	1.0000
19:35065865:CAG:C	acceptor_loss	1.0000
19:35065866:A:AG	acceptor_gain	1.0000
19:35065866:AG:A	acceptor_gain	1.0000
19:35065866:AGGGC:A	acceptor_gain	1.0000
19:35065867:G:GT	acceptor_gain	1.0000
19:35065867:GG:G	acceptor_gain	1.0000
19:35065867:GGGC:G	acceptor_gain	1.0000
19:35065867:GGGCG:G	acceptor_gain	1.0000
19:35066024:GCCA:G	donor_gain	1.0000
19:35050017:GGAT:G	donor_gain	0.9900

AlphaMissense

2688 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35060418:T:A	W176R	1.000
19:35060418:T:C	W176R	1.000
19:35060455:G:A	C188Y	1.000
19:35060503:G:A	C204Y	1.000
19:35060504:C:G	C204W	1.000
19:35060651:G:C	W215C	1.000
19:35060651:G:T	W215C	1.000
19:35060775:G:C	D257H	1.000
19:35060776:A:C	D257A	1.000
19:35060776:A:G	D257G	1.000
19:35060776:A:T	D257V	1.000
19:35065324:T:A	W296R	1.000
19:35065324:T:C	W296R	1.000
19:35065326:G:C	W296C	1.000
19:35065326:G:T	W296C	1.000
19:35065327:G:T	G297C	1.000
19:35065328:G:T	G297V	1.000
19:35065595:T:A	C322S	1.000
19:35065595:T:C	C322R	1.000
19:35065596:G:A	C322Y	1.000
19:35065596:G:C	C322S	1.000
19:35065643:T:A	C338S	1.000
19:35065643:T:C	C338R	1.000
19:35065644:G:A	C338Y	1.000
19:35065644:G:C	C338S	1.000
19:35065645:T:G	C338W	1.000
19:35065676:T:A	C349S	1.000
19:35065676:T:C	C349R	1.000
19:35065677:G:A	C349Y	1.000
19:35065677:G:C	C349S	1.000

dbSNP variants (sampled 300 via entrez): RS1000117221 (19:35040367 G>A), RS1000191245 (19:35041447 A>G), RS1000218499 (19:35063143 A>C,G), RS1000317569 (19:35056808 T>A), RS1000531757 (19:35061636 C>T), RS1000598324 (19:35062848 A>C), RS1000656564 (19:35058461 T>C), RS1000667489 (19:35045335 T>G), RS1000770212 (19:35049342 G>A,T), RS1000783693 (19:35064245 T>C), RS1000833033 (19:35050473 A>G,T), RS1001003290 (19:35052117 C>T), RS1001184652 (19:35048012 A>G), RS1001380376 (19:35066568 G>A), RS1001597809 (19:35044525 G>A,T)

Disease associations

OMIM: gene MIM:142440 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001699_14	Serum albumin levels	2.000000e-13
GCST001699_5	Serum albumin levels	4.000000e-18
GCST001699_8	Serum albumin levels	3.000000e-15
GCST003681_19	C-reactive protein levels or triglyceride levels (pleiotropy)	4.000000e-08
GCST005989_32	Serum total protein levels	1.000000e-11
GCST008790_56	Urinary albumin-to-creatinine ratio	6.000000e-12
GCST008792_8	Urinary albumin-to-creatinine ratio in diabetes	3.000000e-08
GCST010173_30	Triglyceride levels	5.000000e-17
GCST010244_247	Triglyceride levels	2.000000e-24
GCST90000025_563	Appendicular lean mass	6.000000e-14
GCST90002400_281	Plateletcrit	4.000000e-10
GCST90002402_558	Platelet count	2.000000e-09
GCST90013406_187	Liver enzyme levels (alkaline phosphatase)	2.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0004530	triglyceride measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004980	appendicular lean mass
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2079849 (SINGLE PROTEIN), CHEMBL3885586 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 129,543 (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
CHEMBL1623	MECLIZINE	4	20,272
CHEMBL608	PROBUCOL	4	30,435
CHEMBL273264	NAFAMOSTAT	3	7,063
CHEMBL48361	DABIGATRAN	3	13,443
CHEMBL590799	CAMOSTAT	3	6,733
CHEMBL87563	GABEXATE	3	2,031
CHEMBL291278	N-METHYL-D-ASPARTIC ACID (NMDA)	2	35,380
CHEMBL46469	ANTHRALIN	2	14,186

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

Binding affinities (BindingDB)

4 measured of 6 human assays (22 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CRA-8696	KI	160 nM
CA-14	KI	19000 nM
2-{5-[amino(iminiumyl)methyl]-6-fluoro-1H-1,3-benzodiazol-2-yl}-6-{[(1S,2S)-2-methylcyclohexyl]oxy}benzen-1-olate	KI	32000 nM
2-amino-5-[(3-hydroxynaphthalene-2-)amido]-1H-1,3-benzodiazol-3-ium	KI	200000 nM

ChEMBL bioactivities

209 potent at pChembl≥5 of 226 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.08	nM	CHEMBL5081575
10.05	Ki	0.09	nM	CHEMBL4454016
9.80	Ki	0.16	nM	CHEMBL4540950
9.77	IC50	0.17	nM	CHEMBL4454016
9.77	IC50	0.17	nM	CHEMBL5558547
9.70	IC50	0.2	nM	CHEMBL5568169
9.68	Ki	0.21	nM	CHEMBL3356591
9.68	Ki	0.21	nM	CHEMBL3356597
9.66	Ki	0.22	nM	CHEMBL3356589
9.57	Ki	0.27	nM	CHEMBL4587327
9.55	Ki	0.28	nM	CHEMBL3356594
9.49	IC50	0.32	nM	CHEMBL4540950
9.48	IC50	0.33	nM	CHEMBL5564865
9.47	Ki	0.34	nM	CHEMBL3356595
9.42	IC50	0.38	nM	CHEMBL5074750
9.39	Ki	0.41	nM	CHEMBL3356590
9.33	Ki	0.47	nM	CHEMBL3356606
9.30	IC50	0.5	nM	CHEMBL4530678
9.28	Ki	0.53	nM	NAFAMOSTAT
9.27	IC50	0.54	nM	CHEMBL5559738
9.26	Ki	0.55	nM	CHEMBL3356600
9.24	Ki	0.58	nM	CHEMBL3356592
9.24	Ki	0.57	nM	CHEMBL3356596
9.22	Ki	0.6	nM	CHEMBL3356599
9.22	IC50	0.6	nM	CHEMBL4469962
9.21	Ki	0.61	nM	CHEMBL3356604
9.17	Ki	0.68	nM	CHEMBL3356603
9.17	Ki	0.67	nM	CHEMBL4464524
9.16	IC50	0.69	nM	CHEMBL5560415
9.08	Ki	0.83	nM	CHEMBL3745775
9.04	IC50	0.91	nM	CHEMBL5560759
9.00	IC50	0.99	nM	CHEMBL5561725
8.98	Ki	1.04	nM	CHEMBL3747482
8.96	Ki	1.1	nM	CHEMBL2086421
8.92	Ki	1.2	nM	CHEMBL3356598
8.92	Ki	1.2	nM	CHEMBL3356605
8.85	Ki	1.4	nM	CHEMBL3356602
8.84	Ki	1.45	nM	CHEMBL3356589
8.77	Ki	1.7	nM	CHEMBL4463174
8.77	IC50	1.7	nM	CHEMBL5083517
8.70	IC50	2	nM	CHEMBL4469506
8.68	Ki	2.1	nM	CHEMBL3356593
8.55	IC50	2.8	nM	CHEMBL5557087
8.54	Ki	2.88	nM	CHEMBL3747468
8.54	Ki	2.91	nM	CHEMBL3746517
8.47	Ki	3.38	nM	CHEMBL404190
8.30	IC50	5	nM	NAFAMOSTAT
8.30	IC50	5	nM	CHEMBL4434900
8.27	IC50	5.4	nM	CHEMBL5092327
8.24	IC50	5.8	nM	CHEMBL5088958

PubChem BioAssay actives

208 with measured affinity, of 260 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,5S,14S)-14-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-[3-(diaminomethylideneamino)propyl]-3,8,15-trioxo-1,4,9-triazacyclopentadecane-5-carboxamide	1810168: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0001	uM
(2S)-2-[[(2S)-2-acetamido-6-aminohexanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1575065: Inhibition of recombinant human C-terminal His10-tagged hepsin catalytic domain preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0001	uM
(2S)-2-[[(2S)-2-acetamido-6-aminohexanoyl]amino]-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0002	uM
(2S)-2-[[(2S)-2-acetamido-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0002	uM
(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(1H-indol-3-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-4-methylpentanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0002	uM
(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-6-amino-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]hexanamide	1575065: Inhibition of recombinant human C-terminal His10-tagged hepsin catalytic domain preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0002	uM
(9S,12S,15S)-15-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-12-(2-methylpropyl)-11,14-dioxo-2-oxa-10,13-diazatricyclo[15.2.2.13,7]docosa-1(19),3,5,7(22),17,20-hexaene-9-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0002	uM
(4E,7S,10S,13S)-13-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-10-(2-methylpropyl)-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0002	uM
(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0003	uM
(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0003	uM
2-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamidobutanoyl]amino]-5-aminopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-N-piperidin-4-yl-1,3-benzothiazole-6-carboxamide	1550525: Inhibition of recombinant human hepsin preincubated for 30 mins followed by Boc-QLR-AMC substrate addition by fluorescence assay	ki	0.0003	uM
(7S,10S,13S)-13-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-10-benzyl-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),15,18-triene-7-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0003	uM
(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanediamide	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0004	uM
(2S)-2-acetamido-6-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]hexanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0004	uM
2-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-6-aminohexanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-1,3-benzothiazole-6-carboxamide	1810168: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0004	uM
(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-6-amino-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]hexanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0005	uM
(7S,10R,13S)-13-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-10-(1H-indol-3-ylmethyl)-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),15,18-triene-7-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0005	uM
[1-acetyl-4-(2-phenylethyl)piperidin-4-yl] N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate;2,2,2-trifluoroacetic acid	1576187: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0005	uM
(4S)-4-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-oxopentanoic acid	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0005	uM
(6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0005	uM
(2S)-2-[[(2S)-2-acetamido-6-aminohexanoyl]amino]-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanediamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0006	uM
(2S)-2-acetamido-6-amino-N-[(2S)-5-(diaminomethylideneamino)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]hexanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0006	uM
(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-N-[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-4-methylpentanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0006	uM
(2S)-2-[[(2S)-2-acetamido-3-(1H-indol-3-yl)propanoyl]amino]-6-amino-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]hexanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0006	uM
(2S)-2-[[(2S,3R)-2-acetamido-3-hydroxybutanoyl]amino]-6-amino-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]hexanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0006	uM
(2S)-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-(methanesulfonamido)pentanediamide	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0006	uM
(2S)-2-acetamido-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanediamide	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0006	uM
(4-benzylpiperidin-4-yl) N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate;2,2,2-trifluoroacetic acid	1576187: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0006	uM
(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-4-methylpentanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0007	uM
4-[[[2-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-6-aminohexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-1,3-benzothiazole-6-carbonyl]amino]methyl]benzoic acid	1550525: Inhibition of recombinant human hepsin preincubated for 30 mins followed by Boc-QLR-AMC substrate addition by fluorescence assay	ki	0.0007	uM
(4Z,7S,10R,13S)-13-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-10-(1H-indol-3-ylmethyl)-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0007	uM
(2S)-2-[[(2S)-2-acetamido-6-aminohexanoyl]amino]-N-[(2S)-1-[[(2R)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1269259: Inhibition of human recombinant hepsin using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition measured for 15 to 120 mins by plate reader analysis	ki	0.0008	uM
(7S,10S,13S)-13-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-10-(2-methylpropyl)-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),15,18-triene-7-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0009	uM
(2S)-2-acetamido-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1269259: Inhibition of human recombinant hepsin using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition measured for 15 to 120 mins by plate reader analysis	ki	0.0010	uM
(4Z,10S,13S,16S)-16-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-13-(2-methylpropyl)-8,12,15-trioxo-2-oxa-7,11,14-triazabicyclo[16.2.2]docosa-1(20),4,18,21-tetraene-10-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0010	uM
(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]pentanediamide	682986: Tight binding inhibition of human hepsin expressed in Drosophila melanogaster S2 cells using Boc-QAR-AMC as substrate incubated for 15 mins prior to substrate addition measured for 30 mins by fluorimetric analysis	ki	0.0011	uM
(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-6-amino-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]hexanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0012	uM
(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-hydroxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-4-methylpentanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0012	uM
(2S)-2-acetamido-N-[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]butanediamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0014	uM
(2S,5S,14S)-14-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-(2-methylpropyl)-3,8,15-trioxo-1,4,9-triazacyclopentadecane-5-carboxamide	1810168: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0017	uM
9H-fluoren-9-ylmethyl N-[(2S)-4-amino-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1,4-dioxobutan-2-yl]carbamate	1575065: Inhibition of recombinant human C-terminal His10-tagged hepsin catalytic domain preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0017	uM
(2-phenyl-1-piperidin-4-ylethyl) N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate;2,2,2-trifluoroacetic acid	1576187: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0020	uM
(2S)-2-acetamido-6-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]hexanamide	1171341: Inhibition of recombinant hepsin (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0021	uM
(7S,10S,13S)-13-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-10-(1H-indol-3-ylmethyl)-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),15,18-triene-7-carboxamide	2081782: Inhibition of C-terminal 10-His tagged human recombinant hepsin (Arg45 to Leu417 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0028	uM
(2S)-2-acetamido-N-[(2S)-1-[[(2R)-5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	1269259: Inhibition of human recombinant hepsin using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition measured for 15 to 120 mins by plate reader analysis	ki	0.0029	uM
(2S)-2-acetamido-N-[(2R)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-methylpentanamide	1269259: Inhibition of human recombinant hepsin using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition measured for 15 to 120 mins by plate reader analysis	ki	0.0029	uM
(2S)-2-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-methylpentanamide	1269259: Inhibition of human recombinant hepsin using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition measured for 15 to 120 mins by plate reader analysis	ki	0.0034	uM
[4-[2-[2-(dimethylamino)-2-oxoethoxy]-2-oxoethyl]phenyl] 4-(diaminomethylideneamino)benzoate	1806088: TMPRSS2 pericellular activity screening assay from Article 10.1038/s41586-022-04661-w: “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”	ki	0.0042	uM
(4-phenylpiperidin-4-yl) N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate;2,2,2-trifluoroacetic acid	1576187: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0050	uM
(3S,6S,14S)-6-acetamido-N-[(2S)-1-[6-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]amino]-1,3-benzothiazol-2-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-(2-methylpropyl)-2,5,8-trioxo-1,4,9-triazacyclotetradecane-14-carboxamide	1810168: Inhibition of recombinant human C-terminal 10-His tagged hepsin (Arg45 to Leu417) expressed in mouse myeloma cells using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0054	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Amitriptyline	increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Cyclosporine	decreases expression, increases expression	3
sodium arsenite	affects methylation, decreases expression	2
Amiodarone	increases expression	2
Chlorpromazine	increases expression	2
Imipramine	increases expression	2
Perhexiline	increases expression	2
Valproic Acid	affects expression, decreases expression	2
Zimeldine	increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects expression	1
chlortoluron	decreases expression	1
ciglitazone	affects binding, increases expression	1
chlorcyclizine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride	increases expression	1
Calcitriol	increases expression	1
Cisplatin	increases expression, affects cotreatment	1
Clomipramine	increases expression	1
Clozapine	increases expression	1
Erythromycin	increases expression	1
Flecainide	increases expression	1

ChEMBL screening assays

33 unique, capped per target: 33 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2090836	Binding	Tight binding inhibition of human hepsin expressed in Drosophila melanogaster S2 cells using Boc-QAR-AMC as substrate incubated for 15 mins prior to substrate addition measured for 30 mins by fluorimetric analysis	Design and synthesis of potent, selective inhibitors of matriptase. — ACS Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B413	LNCaP-17	Cancer cell line	Male
CVCL_B414	LNCaP-34	Cancer cell line	Male

Clinical trials (associated diseases)

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