TMPRSS2

Summary

TMPRSS2 (transmembrane serine protease 2, HGNC:11876) is a protein-coding gene on chromosome 21q22.3, encoding Transmembrane protease serine 2 (O15393). Plasma membrane-anchored serine protease that cleaves at arginine residues.

This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, a receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Serine proteases are known to be involved in many physiological and pathological processes. This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. This protein also facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. Viruses found to use this protein for cell entry include Influenza virus and the human coronaviruses HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2 (COVID-19 virus). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 7113 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 34 total
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_005656

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11876
Approved symbol	TMPRSS2
Name	transmembrane serine protease 2
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	PRSS10
Ensembl gene	ENSG00000184012
Ensembl biotype	protein_coding
OMIM	602060
Entrez	7113

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 33 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000332149, ENST00000398585, ENST00000424093, ENST00000454499, ENST00000455813, ENST00000458356, ENST00000463138, ENST00000469395, ENST00000489201, ENST00000676973, ENST00000677680, ENST00000678171, ENST00000678348, ENST00000678617, ENST00000678743, ENST00000678959, ENST00000679016, ENST00000679054, ENST00000679181, ENST00000679263, ENST00000864262, ENST00000864263, ENST00000864264, ENST00000864265, ENST00000864266, ENST00000864267, ENST00000864268, ENST00000864269, ENST00000864270, ENST00000864271, ENST00000864272, ENST00000864273, ENST00000864274, ENST00000864275, ENST00000864276, ENST00000864277, ENST00000966230, ENST00000966231, ENST00000966232, ENST00000966233

RefSeq mRNA: 3 — MANE Select: NM_005656 NM_001135099, NM_001382720, NM_005656

CCDS: CCDS33564, CCDS54486, CCDS93100

Canonical transcript exons

ENST00000332149 — 14 exons

Exon	Start	End
ENSE00001291248	41473325	41473496
ENSE00001296629	41508081	41508158
ENSE00001296879	41479172	41479282
ENSE00001308618	41488394	41488513
ENSE00001309041	41470648	41470743
ENSE00001310536	41471806	41471981
ENSE00001319118	41476577	41476620
ENSE00001324661	41468396	41468538
ENSE00001328752	41480476	41480602
ENSE00001919654	41464305	41466153
ENSE00003500399	41489507	41489593
ENSE00003502036	41498119	41498189
ENSE00003786558	41467734	41467886
ENSE00003788834	41494356	41494578

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 98.78.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1010 / max 241.3942, expressed in 362 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190562	2.6714	327
190561	0.4240	238
190563	0.0055	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.78	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.19	gold quality
colonic mucosa	UBERON:0000317	98.07	gold quality
body of pancreas	UBERON:0001150	97.91	gold quality
rectum	UBERON:0001052	97.55	gold quality
esophagus squamous epithelium	UBERON:0006920	95.51	gold quality
prostate gland	UBERON:0002367	94.95	gold quality
metanephros cortex	UBERON:0010533	94.70	gold quality
lower esophagus mucosa	UBERON:0035834	94.45	gold quality
parotid gland	UBERON:0001831	94.33	gold quality
epithelium of esophagus	UBERON:0001976	93.93	gold quality
duodenum	UBERON:0002114	93.75	gold quality
ileal mucosa	UBERON:0000331	93.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.04	gold quality
pancreas	UBERON:0001264	92.53	gold quality
pylorus	UBERON:0001166	92.26	gold quality
upper lobe of left lung	UBERON:0008952	91.97	gold quality
saliva-secreting gland	UBERON:0001044	91.75	gold quality
upper lobe of lung	UBERON:0008948	91.73	gold quality
cardia of stomach	UBERON:0001162	91.26	gold quality
gall bladder	UBERON:0002110	91.23	gold quality
minor salivary gland	UBERON:0001830	91.13	gold quality
transverse colon	UBERON:0001157	90.54	gold quality
stomach	UBERON:0000945	90.23	gold quality
adult mammalian kidney	UBERON:0000082	90.00	gold quality
body of stomach	UBERON:0001161	89.97	gold quality
type B pancreatic cell	CL:0000169	89.92	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.92	gold quality
right lung	UBERON:0002167	89.69	gold quality
esophagus mucosa	UBERON:0002469	89.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	190.68
E-CURD-119	yes	32.91
E-ANND-3	yes	23.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
HGF	Activation

Upstream regulators (CollecTRI, top): AR, ERG, ESR1, ESR2, NCOA3, NKX3-1, VDR

miRNA regulators (miRDB)

63 targeting TMPRSS2, 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-4262	100.00	73.26	3931
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721

Literature-anchored findings (GeneRIF, showing 40)

• present study describes how TMPRSS2 may contribute to prostate tumour metastasis via the activation of PAR-2 (PMID:15537383)
• Data show the presence of the TMPRSS2/ERG gene fusion is common in prostate adenocarcinoma. (PMID:16575875)
• Dysregulation of ETS family members through fusions with TMRPSS2 may be an initiating event in prostate cancer development. (PMID:16585160)
• genomic microdeletion of chromosome 21 is associated with rearrangement, as shown by FISH analysis of TMPRSS2/ERG fusions in prostate cancer (PMID:16820092)
• TMPRSS2 and HAT are candidates for proteolytic activation of influenza viruses in vivo (PMID:16973594)
• demonstrate for the first time that the TMPRSS2-ERG fusion gene can be detected in a proportion of HGPIN lesions and that this molecular rearrangement is an early event that may precede chromosome-level alterations in prostate carcinogenesis (PMID:17032499)
• Gene is deleted in gastric and colorectal cancers. (PMID:17367471)
• findings show that the TMPRSS2-ERG fusion is common in prostate cancer and that the related TMPRSS2-ETV1 fusion is very rare; frequency of ERG-fusions in the present study is somewhat lower than previously observed (PMID:17390040)
• TMPRSS2:ERG prostate cancer gene fusion may lead to haploinsufficiency or additional fusion events. (PMID:17584912)
• TMPRSS2-ERV1 fusion protein was found in 1/82 prostate neoplasms. TMPRSS2-ERG fusion protein was found in 35/82 prostate neoplasms. (PMID:17632455)
• presence/absence of Alu family consensus sequence in the introns of TMPRSS2 and ERG correlates with the presence/absence of fusion transcripts and indicates consensus sequence may be involved in prostate cancer (PMID:17654723)
• Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma. (PMID:17804708)
• Frequent presence of the TMPRSS2-ERG in index tumors suggests critical roles of ERG alterations in the onset and progression of a large subset of prostate cancer. (PMID:18065961)
• A TMPRSS2:ETV5 gene fusion was identified in prostate cancer. (PMID:18172298)
• further study is required to address association between TMPRSS2:ERG fusion and prostate cancer metastasis, detection of genomic truncation of the ERG gene could be useful for monitoring appearance of CTC and potential for prostate cancer metastasis (PMID:18385909)
• Detection of ETS fusion gene by RT-PCR is feasible on formalin-fixed and paraffin-embedded samples. (PMID:18474293)
• TMPRSS2-ERG with interstitial deletion is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease (PMID:18483239)
• the detection of isolated TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies. (PMID:18519767)
• The TMPRSS2:ERG rearrangement can be found in about one third of prostate cancers. A subgroup of prostate cancer patients with a good prognosis may be identified by the rearrangement (PMID:18519769)
• Efficient multiplication of metapneumovirus in Vero cells expressing TMPRSS2 is reported. (PMID:18562527)
• Information of TMPRSS2:ERG fusion status improved prognostification of the multigene model. (PMID:18583469)
• analysis of the TMPRSS2-ERG splice variants in prostate cancer (PMID:18676740)
• TMPRSS2-ERG gene fusion has a role in prostate cancer characteristics and outcomes (PMID:18694509)
• TMPRSS2/ERG fusion isoforms have variable biological activities promoting tumor initiation and progression. (PMID:18922926)
• TMPRSS2-ERG fusion is frequently observed in Gleason pattern 3 prostate cancer in a Canadian cohort. (PMID:19029822)
• study detected the TMPRSS2-ERG fusion in 44 (59%) familial prostate cancer patients; findings revealed several loci located on chromosomes #9, #18, and X that were suggestive of linkage to the TMPRSS2-ERG fusion-positive prostate cancer phenotype (PMID:19147579)
• The authors provide evidence that TMPRSS2 and TMPRSS4 activate the 1918 HA by cleavage and therefore may promote viral spread in lung tissue. (PMID:19158246)
• Translocation of TMPRSS2-ERG is not associated with outcome and the aggressive clinical features associated with copy number increas in prostate cancer. (PMID:19190343)
• the up-regulation of TMPRSS2 and the down-regulation of KLK11 in advanced and more aggressive tumors may open the feasibility of being used as biomarkers distinguishing the tumor aggressiveness as well as novel prognostic indicators for prostate cancer. (PMID:19242826)
• We found that TMPRSS2-ERG gene fusion is associated with the zonal origin of prostate cancer. (PMID:19396154)
• TMPRSS2:ERG fusion was identified in 83% (15/18), 71% (5/7), 50% (9/18), 33% (3/9), and 29% (5/17) of mucinous, small cell, ductal, glomeruloid, and foamy gland prostate carcinomas, respectively (PMID:19465903)
• Results suggest that androgen ablation inhibits the expression of TMPRSS2:ERG, and that tumors in which pre-surgery androgen ablation fails to suppress expression of the fusion gene have a higher risk of recurrence. (PMID:19494719)
• Rsults show that TMPRSS2-ERG rearrangement is common among North American men who have prostate cancer on biopsy. (PMID:19584163)
• A significantly reduced expression of TMPRSS2 was evident in malignant cells harboring TMPRSS2-ERG fusion, but not in prostate cancer cells without TMPRSS2-ERG fusion, further defining these two genetically distinct types of prostate cancer. (PMID:19597533)
• This study demonstrates that most ERG-overexpressing prostate cancers harbor hormonally regulated TMPRSS2-ERG, SLC45A3-ERG, or NDRG1-ERG fusions (PMID:19649210)
• these findings contribute to the increasing elucidation of the role of TMPRSS2:ERG in the development of prostate cancer. (PMID:19664128)
• SMARCD1/BAF60a is an androgen receptor cofactor that modulates TMPRSS2 expression (PMID:19762545)
• study shows in prostate cancer cells, androgen signaling induces proximity of the TMPRSS2 & ERG genomic loci, located on chromosome 21q22.2; exposure to gamma irradiation, causing DNA double-strand breaks, facilitates formation of TMPRSS2-ERG gene fusion (PMID:19933109)
• TMPRSS2-ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies. (PMID:20068566)
• This is the first study to report concurrent TMPRSS2 and SLC45A3 rearrangements in the same tumor focus in prostate cancer (PMID:20118910)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmprss2	ENSDARG00000098686
mus_musculus	Tmprss2	ENSMUSG00000000385
rattus_norvegicus	Tmprss2	ENSRNOG00000001976
drosophila_melanogaster	Sb	FBGN0003319
drosophila_melanogaster	CG17242	FBGN0250841

Paralogs (17): PRSS22 (ENSG00000005001), PRSS21 (ENSG00000007038), TMPRSS11E (ENSG00000087128), HPN (ENSG00000105707), TMPRSS13 (ENSG00000137747), ST14 (ENSG00000149418), TMPRSS11D (ENSG00000153802), TMPRSS15 (ENSG00000154646), TMPRSS3 (ENSG00000160183), TMPRSS5 (ENSG00000166682), TMPRSS7 (ENSG00000176040), TMPRSS9 (ENSG00000178297), TMPRSS11B (ENSG00000185873), TMPRSS6 (ENSG00000187045), TMPRSS11A (ENSG00000187054), TMPRSS11F (ENSG00000198092), PRSS41 (ENSG00000215148)

Protein

Protein identifiers

Transmembrane protease serine 2 — O15393 (reviewed: O15393)

Alternative names: Serine protease 10

All UniProt accessions (11): A0A7I2V3D1, A0A7I2V474, A0A7I2V509, A0A7I2V5F9, A0A7I2V5N2, A0A7I2V650, A0A7I2YQ98, C9J5Y1, C9JB05, C9JKZ3, O15393

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane-anchored serine protease that cleaves at arginine residues. Participates in proteolytic cascades of relevance for the normal physiologic function of the prostate. Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells. In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia. (Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry. The cleavage of SARS-COV2 spike glycoprotein occurs between the S2 and S2’ site. Upon SARS-CoV-2 infection, increases syncytia formation by accelerating the fusion process. Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity. (Microbial infection) Receptor for human coronavirus HKU1-CoV, acts synergistically with disialoside glycans to facilitate the entry of the virus. After binding to cell-surface disialoside glycans, the viral S protein interacts with the inactive form of TMPRSS2 and inhibits its protease activity.

Subunit / interactions. The catalytically active form interacts with ACE2.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Expressed in several tissues that comprise large populations of epithelial cells with the highest level of transcripts measured in the prostate gland. Expressed in type II pneumocytes in the lung (at protein level). Expressed strongly in small intestine. Also expressed in colon, stomach and salivary gland. Coexpressed with ACE2 within lung type II pneumocytes, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells (Ref.21).

Post-translational modifications. Proteolytically processed; by an autocatalytic mechanism. Autocleavage induces active conformation.

Induction. By androgenic hormones in vivo.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15393-1	1	yes
O15393-2	2

RefSeq proteins (3): NP_001128571, NP_001369649, NP_005647* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR023415	LDLR_class-A_CS	Conserved_site
IPR033116	TRYPSIN_SER	Active_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00089, PF15494

Enzyme classification (BRENDA):

• EC 3.4.21.B60 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (115 total): strand 30, mutagenesis site 22, helix 10, turn 9, sequence variant 9, disulfide bond 9, binding site 5, sequence conflict 5, active site 3, domain 3, chain 2, glycosylation site 2, topological domain 2, site 1, splice variant 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

34 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8V04	X-RAY DIFFRACTION	1.58
8S0L	X-RAY DIFFRACTION	1.8
9JD1	X-RAY DIFFRACTION	1.9
7MEQ	X-RAY DIFFRACTION	1.95
9JD0	X-RAY DIFFRACTION	2
9U8G	X-RAY DIFFRACTION	2
9E83	X-RAY DIFFRACTION	2.07
8V1F	X-RAY DIFFRACTION	2.19
8S0N	X-RAY DIFFRACTION	2.3
7Y0E	X-RAY DIFFRACTION	2.39
8HD8	X-RAY DIFFRACTION	2.4
9IZN	X-RAY DIFFRACTION	2.4
7XYD	X-RAY DIFFRACTION	2.58
7Y0F	X-RAY DIFFRACTION	2.6
8Y1D	ELECTRON MICROSCOPY	2.7
8Y1E	ELECTRON MICROSCOPY	2.7
9JCX	X-RAY DIFFRACTION	2.75
9Z3J	ELECTRON MICROSCOPY	2.8
8VGT	ELECTRON MICROSCOPY	2.9
8JI0	ELECTRON MICROSCOPY	3
8Y8B	ELECTRON MICROSCOPY	3.01
8Y88	ELECTRON MICROSCOPY	3.03
8Y7X	ELECTRON MICROSCOPY	3.09
9K3T	ELECTRON MICROSCOPY	3.15
8Y8A	ELECTRON MICROSCOPY	3.19
8JHZ	ELECTRON MICROSCOPY	3.2
9OPR	ELECTRON MICROSCOPY	3.2
8YOY	ELECTRON MICROSCOPY	3.21
8Y7Y	ELECTRON MICROSCOPY	3.24
8Y87	ELECTRON MICROSCOPY	3.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15393-F1	79.72	0.51

Antibody-complex structures (SAbDab): 7 — 8S0L, 8S0M, 8S0N, 9JD0, 9JD1, 9K3T, 9U8G

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 (4): 345 (charge relay system); 441 (charge relay system); 255–256 (cleavage; by autolysis); 296 (charge relay system)

Ligand- & substrate-binding residues (5): 131; 134; 136; 144; 145

Disulfide bonds (9): 113–126, 120–139, 133–148, 172–231, 185–241, 244–365, 281–297, 410–426, 437–465

Glycosylation sites (2): 213, 249

Mutagenesis-validated functional residues (22):

Position	Phenotype
255	loss of cleavage. no effect on hku1-cov viral entry.
316	no effect on catalytic activity or hku1-cov viral entry.
340	no effect on hku1-cov viral entry.
341	no effect on catalytic activity or hku1-cov viral entry.
409	no effect on catalytic activity. reduces hku1-cov viral entry.
412	no effect on catalytic activity. reduces hku1-cov viral entry.
413	no effect on catalytic activity. reduces hku1-cov viral entry.
414	no effect on catalytic activity. almost abolishes s protein-binding and hku1-cov viral entry.
415	no effect on hku1-cov viral entry.
416	no effect on catalytic activity. almost abolishes hku1-cov viral entry.
417	no effect on catalytic activity. almost abolishes hku1-cov viral entry.
419	no effect on catalytic activity. abolishes hku1-cov viral entry.
430	no effect on catalytic activity. abolishes hku1-cov viral entry.
431	no effect on catalytic activity or hku1-cov viral entry.
433	no effect on catalytic activity or hku1-cov viral entry.
441	loss of activity. no effect on hku1-cov viral entry.
461	no effect on catalytic activity. abolishes hku1-cov s protein-binding and viral entry.
463	no effect on catalytic activity. reduces hku1-cov viral entry.
467	no effect on catalytic activity. reduces hku1-cov viral entry.
468	no effect on hku1-cov viral entry.
469	no effect on catalytic activity. reduces hku1-cov viral entry.
470	no effect on catalytic activity. abolishes hku1-cov s protein-binding and viral entry.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9678110	Attachment and Entry
R-HSA-9694614	Attachment and Entry
R-HSA-9733458	Induction of Cell-Cell Fusion

MSigDB gene sets: 172 (showing top): MODULE_172, MODULE_64, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_BIOLOGICAL_PROCESS_INVOLVED_IN_SYMBIOTIC_INTERACTION, MODULE_109, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, CAIRO_HEPATOBLASTOMA_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_HOST, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_VIRAL_LIFE_CYCLE, NELSON_RESPONSE_TO_ANDROGEN_UP, GFI1_01, MULLIGHAN_NPM1_SIGNATURE_3_DN

GO Biological Process (6): proteolysis (GO:0006508), protein autoprocessing (GO:0016540), positive regulation of viral entry into host cell (GO:0046598), entry receptor-mediated virion attachment to host cell (GO:0098670), viral translation (GO:0019081), symbiont-mediated induction of syncytium formation (GO:0060141)

GO Molecular Function (5): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1
Late SARS-CoV-2 Infection Events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein metabolic process	1
protein processing	1
regulation of viral entry into host cell	1
symbiont entry into host cell	1
positive regulation by symbiont of entry into host	1
positive regulation of viral life cycle	1
receptor-mediated virion attachment to host cell	1
viral process	1
viral gene expression	1
symbiont-mediated perturbation of host cellular process	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
membrane	1
cell periphery	1
extracellular vesicle	1

Protein interactions and networks

STRING

2606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMPRSS2	ACE2	Q9BYF1	999
TMPRSS2	ETV1	P50549	942
TMPRSS2	ADAM17	P78536	937
TMPRSS2	ERG	P11308	921
TMPRSS2	FURIN	P09958	898
TMPRSS2	AR	P10275	886
TMPRSS2	DPP4	P27487	874
TMPRSS2	CTSL	P07711	864
TMPRSS2	ACE	P12821	863
TMPRSS2	SLC45A3	Q96JT2	857
TMPRSS2	BSG	P35613	825
TMPRSS2	CD9	P21926	805
TMPRSS2	ETV4	P43268	782
TMPRSS2	CTSB	P07858	763
TMPRSS2	AMACR	Q9UHK6	744

IntAct

9 interactions, top by confidence:

A	B	Type	Score
SERPINA1	TMPRSS2	psi-mi:“MI:0194”(cleavage reaction)	0.560
TMPRSS2	SERPINA1	psi-mi:“MI:0194”(cleavage reaction)	0.560
TMPRSS2	ACE2	psi-mi:“MI:0915”(physical association)	0.460
TMPRSS2	ACE2	psi-mi:“MI:0403”(colocalization)	0.460
	TMPRSS2	psi-mi:“MI:0194”(cleavage reaction)	0.440
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (433): TMPRSS2 (Biochemical Activity), TMPRSS2 (Affinity Capture-RNA), TMPRSS2 (Affinity Capture-MS), S (Biochemical Activity), S (Biochemical Activity), S (Biochemical Activity), S (Biochemical Activity), ACE2 (Biochemical Activity), ACE2 (Affinity Capture-Western), TMPRSS2 (Affinity Capture-Western), TMPRSS2 (Two-hybrid), TMPRSS2 (Two-hybrid), TMPRSS2 (Two-hybrid), TMPRSS2 (Two-hybrid), TMPRSS2 (Two-hybrid)

ESM2 similar proteins: A0A182C2Z2, A0A1S4GMJ4, A6MFK8, B5G6G5, O15393, O60235, O70244, O96900, P00750, P05156, P11214, P19637, P25723, P29598, P79953, P81428, P82807, P83370, P86091, P97435, P98072, P98073, P98074, P98119, P98121, Q05589, Q14C59, Q17800, Q20176, Q4QXT9, Q58L93, Q58L94, Q5QSK2, Q5R5A4, Q5R8J0, Q61129, Q66TN7, Q6DIV5, Q6IE14, Q6ZMR5

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

9 interactions.

A	Effect	B	Mechanism
AR	“up-regulates quantity by expression”	TMPRSS2	“transcriptional regulation”
TMPRSS2	“up-regulates activity”	S	cleavage
Camostat	“down-regulates activity”	TMPRSS2	“chemical inhibition”
nafamostat	“down-regulates activity”	TMPRSS2	“chemical inhibition”
“Camostat mesylate”	“down-regulates activity”	TMPRSS2	“chemical inhibition”
TMPRSS2	“up-regulates quantity by expression”	HGF	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	7
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2409 predictions. Top by Δscore:

Variant	Effect	Δscore
21:41468391:ATTAC:A	donor_loss	1.0000
21:41468392:TTACC:T	donor_loss	1.0000
21:41468393:TACC:T	donor_loss	1.0000
21:41468394:A:C	donor_loss	1.0000
21:41468395:C:A	donor_loss	1.0000
21:41468534:CTTCC:C	acceptor_gain	1.0000
21:41468535:TTCC:T	acceptor_gain	1.0000
21:41468537:CC:C	acceptor_gain	1.0000
21:41468537:CCCTA:C	acceptor_loss	1.0000
21:41468538:CC:C	acceptor_gain	1.0000
21:41468539:C:CC	acceptor_gain	1.0000
21:41468539:CTAA:C	acceptor_loss	1.0000
21:41470741:GGT:G	acceptor_gain	1.0000
21:41470743:TC:T	acceptor_loss	1.0000
21:41470744:C:CA	acceptor_loss	1.0000
21:41470744:C:CC	acceptor_gain	1.0000
21:41470745:T:A	acceptor_loss	1.0000
21:41470751:A:T	acceptor_gain	1.0000
21:41471801:CGTA:C	donor_loss	1.0000
21:41471804:A:AC	donor_gain	1.0000
21:41471805:C:CC	donor_gain	1.0000
21:41471914:CA:C	acceptor_gain	1.0000
21:41471982:C:CC	acceptor_gain	1.0000
21:41473314:C:A	donor_gain	1.0000
21:41473320:CATA:C	donor_loss	1.0000
21:41473321:ATAC:A	donor_loss	1.0000
21:41473322:TACTT:T	donor_loss	1.0000
21:41473323:A:AC	donor_gain	1.0000
21:41473324:C:CA	donor_gain	1.0000
21:41473324:CT:C	donor_gain	1.0000

AlphaMissense

3218 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:41467807:C:G	C465S	0.999
21:41467808:A:T	C465S	0.999
21:41467818:C:A	W461C	0.999
21:41467818:C:G	W461C	0.999
21:41467882:T:A	D440V	0.999
21:41468399:G:C	C437W	0.999
21:41468400:C:G	C437S	0.999
21:41468400:C:T	C437Y	0.999
21:41468401:A:T	C437S	0.999
21:41468432:A:C	C426W	0.999
21:41468433:C:G	C426S	0.999
21:41468434:A:T	C426S	0.999
21:41468481:C:G	C410S	0.999
21:41468482:A:T	C410S	0.999
21:41470667:C:A	W384C	0.999
21:41470667:C:G	W384C	0.999
21:41470669:A:G	W384R	0.999
21:41470669:A:T	W384R	0.999
21:41467837:A:G	L455P	0.998
21:41467867:A:G	L445P	0.998
21:41467882:T:G	D440A	0.998
21:41468400:C:A	C437F	0.998
21:41468433:C:T	C426Y	0.998
21:41471847:T:A	D345V	0.998
21:41471847:T:G	D345A	0.998
21:41473382:C:G	C281S	0.998
21:41473382:C:T	C281Y	0.998
21:41473383:A:T	C281S	0.998
21:41473417:C:A	W269C	0.998
21:41473417:C:G	W269C	0.998

dbSNP variants (sampled 300 via entrez): RS1000072663 (21:41471057 A>G), RS1000133479 (21:41509398 A>C), RS1000165575 (21:41492701 G>T), RS1000232927 (21:41497522 A>C), RS1000265518 (21:41497191 T>C,G), RS1000318387 (21:41486618 A>G), RS1000433462 (21:41477644 A>G), RS1000516135 (21:41493878 C>T), RS1000568527 (21:41494141 C>G,T), RS1000802839 (21:41490455 T>C), RS1000849324 (21:41498331 C>A), RS1000854682 (21:41507533 A>G,T), RS1000873787 (21:41491799 G>A), RS1000877575 (21:41482689 C>T), RS1000986325 (21:41477371 C>T)

Disease associations

OMIM: gene MIM:602060 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002337_60	Amyotrophic lateral sclerosis (sporadic)	2.000000e-09
GCST002606_24	Prostate cancer	3.000000e-07
GCST002606_6	Prostate cancer	3.000000e-08
GCST90013407_112	Liver enzyme levels (gamma-glutamyl transferase)	3.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1795140 (SINGLE PROTEIN), CHEMBL6195526 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 77,295 (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
CHEMBL169901	DEBRISOQUIN	4	1,047
CHEMBL506247	TANNIC ACID	4	25,753
CHEMBL55	PENTAMIDINE	4	27,049
CHEMBL23013	PROPAMIDINE	3	5,100
CHEMBL273264	NAFAMOSTAT	3	7,063
CHEMBL46618	OTAMIXABAN	3	526
CHEMBL590799	CAMOSTAT	3	6,733
CHEMBL87563	GABEXATE	3	2,031
CHEMBL35241	DIMINAZENE	2	1,993

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs383510	TMPRSS2		0.00	0
rs12329760	TMPRSS2		0.00	0
rs2070788	TMPRSS2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
N-0920	Inhibition	9.46	pIC50
MM3122	Inhibition	9.37	pIC50
I-432	Inhibition	9.05	pKi
N-0385	Inhibition	8.72	pIC50
compound 5 [PMID: 21741839]	Inhibition	7.7	pKi
nafamostat	Inhibition	7.0	pIC50
otamixaban	Inhibition	6.21	pIC50
camostat	Inhibition	6.0	pIC50

ChEMBL bioactivities

75 potent at pChembl≥5 of 82 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	Ki	0.03	nM	CHEMBL6174967
10.02	Ki	0.095	nM	CHEMBL6144144
9.96	Ki	0.11	nM	CHEMBL6172535
9.76	Ki	0.172	nM	CHEMBL5532456
9.62	Ki	0.24	nM	CHEMBL6163067
9.46	IC50	0.35	nM	CHEMBL6174967
9.30	IC50	0.5	nM	NAFAMOSTAT
9.28	Ki	0.53	nM	CHEMBL6163291
9.23	IC50	0.59	nM	CHEMBL6172535
9.23	IC50	0.59	nM	CHEMBL6174967
9.21	IC50	0.62	nM	CHEMBL6150218
9.18	IC50	0.66	nM	CHEMBL6164098
9.18	IC50	0.66	nM	CHEMBL6176630
9.17	IC50	0.67	nM	CHEMBL5532456
9.13	IC50	0.74	nM	CHEMBL6167030
9.06	IC50	0.87	nM	CHEMBL6172466
9.06	IC50	0.87	nM	CHEMBL6163067
9.05	Ki	0.9	nM	CHEMBL3219079
9.05	IC50	0.89	nM	CHEMBL6144144
9.01	IC50	0.98	nM	CHEMBL5560415
9.00	Ki	1	nM	CHEMBL3219087
9.00	IC50	1	nM	NAFAMOSTAT
9.00	IC50	1	nM	CHEMBL6159875
8.92	IC50	1.2	nM	CHEMBL5558547
8.92	IC50	1.2	nM	CHEMBL5557551
8.89	IC50	1.3	nM	CHEMBL6165833
8.85	IC50	1.4	nM	CHEMBL5982921
8.85	IC50	1.4	nM	CHEMBL6142154
8.85	IC50	1.4	nM	CHEMBL6132920
8.85	IC50	1.4	nM	CHEMBL6160234
8.77	IC50	1.7	nM	CHEMBL5620212
8.72	IC50	1.9	nM	CHEMBL5532456
8.62	IC50	2.4	nM	CHEMBL6163291
8.60	IC50	2.5	nM	CHEMBL5555448
8.52	Ki	3	nM	CHEMBL3219102
8.52	Ki	3	nM	CHEMBL3219101
8.52	Ki	3	nM	CHEMBL3219100
8.52	Ki	3	nM	CHEMBL3219103
8.52	IC50	3	nM	CHEMBL4081543
8.49	IC50	3.2	nM	CHEMBL6164215
8.43	IC50	3.7	nM	CHEMBL5559738
8.41	IC50	3.9	nM	CAMOSTAT
8.38	IC50	4.2	nM	CHEMBL5559988
8.38	IC50	4.2	nM	CHEMBL5619680
8.01	IC50	9.8	nM	CHEMBL5560759
7.96	IC50	11	nM	CHEMBL5568169
7.92	Ki	12	nM	CHEMBL6172535
7.92	Ki	12	nM	CHEMBL6144144
7.92	Ki	12	nM	CHEMBL6163067
7.92	Ki	12	nM	CHEMBL6174967

PubChem BioAssay actives

52 with measured affinity, of 76 total; 49 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
(6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate	2067026: Inhibition of human TMPRSS2	ic50	0.0005	uM
3-[(2S)-3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(2,4-dichlorophenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	1916558: Inhibition of TMPRSS2 (unknown origin) expressed in Escherichia coli BL21 (DE3) using H-D cyclohexylalanine-Pro-Arg-AM as substrate by Dixon method	ki	0.0009	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 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
3-[(2S)-3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(2,4-dimethoxyphenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	1916558: Inhibition of TMPRSS2 (unknown origin) expressed in Escherichia coli BL21 (DE3) using H-D cyclohexylalanine-Pro-Arg-AM as substrate by Dixon method	ki	0.0010	uM
(8S,11S,14S)-14-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-11-(2-methylpropyl)-10,13-dioxo-2-oxa-9,12-diazatricyclo[14.2.2.23,6]docosa-1(18),3(22),4,6(21),16,19-hexaene-8-carboxamide	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0012	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0012	uM
N-[7-[(2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-4-(diaminomethylideneamino)benzamide	2128376: Inhibition of human TMPRSS2 using fluorogenic substrate preincubated with enzyme in dark for 45 mins followed by substrate addition and measured after 10 mins by fluorogenic assay	ic50	0.0017	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.”	ic50	0.0019	uM
(4Z,11S,14S,17S)-17-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-14-(2-methylpropyl)-8,13,16-trioxo-2-oxa-7,12,15-triazabicyclo[17.2.2]tricosa-1(21),4,19,22-tetraene-11-carboxamide	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0025	uM
1-[2-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(2,4-dimethoxyphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]ethyl]-3-methylurea	1916558: Inhibition of TMPRSS2 (unknown origin) expressed in Escherichia coli BL21 (DE3) using H-D cyclohexylalanine-Pro-Arg-AM as substrate by Dixon method	ki	0.0030	uM
1-[2-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(2,4-dichlorophenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]ethyl]-3-methylurea	1916558: Inhibition of TMPRSS2 (unknown origin) expressed in Escherichia coli BL21 (DE3) using H-D cyclohexylalanine-Pro-Arg-AM as substrate by Dixon method	ki	0.0030	uM
1-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(2,4-dimethoxyphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-3-cyclohexylurea	1916558: Inhibition of TMPRSS2 (unknown origin) expressed in Escherichia coli BL21 (DE3) using H-D cyclohexylalanine-Pro-Arg-AM as substrate by Dixon method	ki	0.0030	uM
1-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(2,4-dichlorophenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-3-cyclohexylurea	1916558: Inhibition of TMPRSS2 (unknown origin) expressed in Escherichia coli BL21 (DE3) using H-D cyclohexylalanine-Pro-Arg-AM as substrate by Dixon method	ki	0.0030	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.”	ic50	0.0031	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0037	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.”	ic50	0.0039	uM
[4-[2-[2-(dimethylamino)-2-oxoethoxy]-2-oxoethyl]phenyl] 4-(diaminomethylideneamino)benzoate	2067026: Inhibition of human TMPRSS2	ic50	0.0039	uM
(2-oxo-4-propan-2-ylchromen-6-yl) 4-(diaminomethylideneamino)benzoate	2128376: Inhibition of human TMPRSS2 using fluorogenic substrate preincubated with enzyme in dark for 45 mins followed by substrate addition and measured after 10 mins by fluorogenic assay	ic50	0.0042	uM
(6R,9S,12S)-12-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-9-(2-methylpropyl)-8,11-dioxo-1,7,10,15,16-pentazabicyclo[12.2.1]heptadeca-14(17),15-diene-6-carboxamide	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0042	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.”	ic50	0.0052	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0098	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0110	uM
(4E,7S,10S,13S)-7-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-10-(2-methylpropyl)-8,11-dioxo-2-oxa-9,12-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-13-carboxamide	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0140	uM
(9S,12S,15S)-9-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-12-(2-methylpropyl)-10,13-dioxo-2-oxa-11,14-diazatricyclo[15.2.2.13,7]docosa-1(19),3,5,7(22),17,20-hexaene-15-carboxamide	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0150	uM
(6S,9S,12R)-6-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-9-(2-methylpropyl)-7,10-dioxo-1,8,11,15,16-pentazabicyclo[12.2.1]heptadeca-14(17),15-diene-12-carboxamide	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0150	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0160	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0160	uM
(2S)-1-[(2R)-2-(benzylsulfonylamino)-5-(diaminomethylideneamino)pentanoyl]-N-[(4-carbamimidoylphenyl)methyl]pyrrolidine-2-carboxamide	610101: Inhibition of recombinant catalytic domain of TMPRSS2 expressed in Escherichia coli using Dcyclohexylalanine- Pro-Arg-AMC as substrate by fluorescence plate reader analysis	ki	0.0200	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	2081779: Inhibition of N-terminal 6His-tagged human recombinant TMPRSS2 (106 to 492 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0220	uM
4-[[[(5R)-5-(benzylsulfonylamino)-8-(diaminomethylideneamino)-4-oxooctan-3-yl]amino]methyl]benzenecarboximidamide	610101: Inhibition of recombinant catalytic domain of TMPRSS2 expressed in Escherichia coli using Dcyclohexylalanine- Pro-Arg-AMC as substrate by fluorescence plate reader analysis	ki	0.0530	uM
4-[[[(4S,6R)-6-(benzylsulfonylamino)-9-(diaminomethylideneamino)-5-oxononan-4-yl]amino]methyl]benzenecarboximidamide	610101: Inhibition of recombinant catalytic domain of TMPRSS2 expressed in Escherichia coli using Dcyclohexylalanine- Pro-Arg-AMC as substrate by fluorescence plate reader analysis	ki	0.0680	uM
2-[4-[4-(diaminomethylideneamino)benzoyl]oxyphenyl]acetic acid	2067026: Inhibition of human TMPRSS2	ic50	0.0700	uM
ethyl 4-[6-(diaminomethylideneamino)hexanoyloxy]benzoate	2067026: Inhibition of human TMPRSS2	ic50	0.1300	uM
methyl (2R,3R)-2-[(3-carbamimidoylphenyl)methyl]-3-[[4-(1-oxidopyridin-1-ium-4-yl)benzoyl]amino]butanoate	2067026: Inhibition of human TMPRSS2	ic50	0.6200	uM
Bromhexine	1803981: titration assay from Article 10.1158/2159-8290.CD-13-1010: “The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.”	ic50	0.7500	uM
(4-methoxycarbonylphenyl) thiophene-2-carboxylate	1803981: titration assay from Article 10.1158/2159-8290.CD-13-1010: “The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.”	ic50	0.9300	uM
Pentamidine	1948587: Inhibition of TMPRSS2 (247 to 492 residues) (unknown origin) peptidase domain expressed in Escherichia coli BL21 (DE3) incubated for 30 mins followed by substrate addition measured after 30 mins by fluorescence based microscopic analysis	ic50	1.2000	uM
4-(4-carbamimidoyl-2-methylphenyl)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzamide	2067026: Inhibition of human TMPRSS2	ic50	1.2400	uM
4-[2-(4-carbamimidoylphenyl)iminohydrazinyl]benzenecarboximidamide	2066691: Inhibition of TMPRSS2 (unknown origin) using Boc-Gln-Ala-Arg-AMC as peptide substrate pre-incubated with compound for 30 mins followed by substrate addition by fluorescence based assay	ic50	1.3500	uM
methyl 2-(7-hydroxy-2-oxochromen-4-yl)acetate	1803981: titration assay from Article 10.1158/2159-8290.CD-13-1010: “The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.”	ic50	1.3700	uM
Tannic Acid	2066684: Inhibition of human recombinant TMPRSS2 using Boc-Gln-Ala-Arg-AMC as peptide substrate pre-incubated with compound for 30 mins followed by substrate addition by fluorescence based assay	ic50	2.3100	uM
4-(4-chlorophenyl)-3-ethyl-N-phenyl-1,3-thiazol-2-imine	1803981: titration assay from Article 10.1158/2159-8290.CD-13-1010: “The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.”	ic50	2.6400	uM
12-bromo-4-ethyl-1,4-diazatetracyclo[7.6.1.05,16.010,15]hexadeca-9(16),10(15),11,13-tetraene	1803981: titration assay from Article 10.1158/2159-8290.CD-13-1010: “The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.”	ic50	2.6800	uM
N-[4-[[3-(dimethylamino)azetidin-1-yl]methyl]-3-(trifluoromethyl)phenyl]-3-nitro-4-(3,3,3-trifluoropropoxy)benzamide	2096902: Inhibition of human recombinant TMPRSS2 using Boc-Gln-Ala-Arg-AMC as peptide substrate pre-incubated with compound for 30 mins followed by substrate addition by fluorescence based assay	ic50	3.3700	uM
N-(2-carbamimidoyl-3,4-dihydro-1H-isoquinolin-6-yl)naphthalene-1-carboxamide	1948592: Inhibition of TMPRSS2 (106 to 492 residues) (unknown origin) using Boc-QAR-AMC as substrate measured for 20 mins by spectrophotometer analysis	ic50	3.4000	uM
N-(2-carbamimidoyl-3,4-dihydro-1H-isoquinolin-6-yl)naphthalene-2-carboxamide	1948592: Inhibition of TMPRSS2 (106 to 492 residues) (unknown origin) using Boc-QAR-AMC as substrate measured for 20 mins by spectrophotometer analysis	ic50	4.0000	uM
N-(2-carbamimidoyl-3,4-dihydro-1H-isoquinolin-6-yl)-4-methylbenzamide	1948592: Inhibition of TMPRSS2 (106 to 492 residues) (unknown origin) using Boc-QAR-AMC as substrate measured for 20 mins by spectrophotometer analysis	ic50	4.0000	uM
N-(2-carbamimidoyl-3,4-dihydro-1H-isoquinolin-6-yl)-4-methoxybenzamide	1948592: Inhibition of TMPRSS2 (106 to 492 residues) (unknown origin) using Boc-QAR-AMC as substrate measured for 20 mins by spectrophotometer analysis	ic50	9.0000	uM
4-[3-(4-carbamimidoylphenoxy)propoxy]benzenecarboximidamide	1948587: Inhibition of TMPRSS2 (247 to 492 residues) (unknown origin) peptidase domain expressed in Escherichia coli BL21 (DE3) incubated for 30 mins followed by substrate addition measured after 30 mins by fluorescence based microscopic analysis	ic50	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Dihydrotestosterone	decreases reaction, increases expression, affects binding, increases reaction, decreases expression	7
Estradiol	decreases expression, increases reaction, affects cotreatment, increases expression	6
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Ethinyl Estradiol	affects expression, decreases expression, increases expression	4
bicalutamide	decreases reaction, increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
Testosterone	decreases reaction, increases expression, affects cotreatment, decreases expression	3
Metribolone	decreases expression, decreases reaction, increases expression	3
bisphenol A	affects expression, affects cotreatment, increases methylation	2
sodium arsenite	affects expression, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Calcitriol	increases expression, affects cotreatment	2
Curcumin	affects binding, decreases reaction, increases reaction, decreases expression	2
Doxorubicin	decreases expression, increases expression	2
Flutamide	decreases reaction, increases expression	2
Nickel	decreases expression	2
Phenobarbital	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	increases expression, affects expression	2
Aflatoxin B1	affects expression, decreases expression	2
Genistein	decreases expression	2
dicrotophos	decreases expression	1
androstane-3,17-dione	increases expression	1
eriodictyol	increases cleavage	1
methylselenic acid	affects expression	1
tetramethrin	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
phentin acetate	affects expression	1

ChEMBL screening assays

28 unique, capped per target: 28 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1810435	Binding	Inhibition of recombinant catalytic domain of TMPRSS2 expressed in Escherichia coli using Dcyclohexylalanine- Pro-Arg-AMC as substrate by fluorescence plate reader analysis	Development of substrate analogue inhibitors for the human airway trypsin-like protease HAT. — Bioorg Med Chem Lett

Cellosaurus cell lines

32 cell lines: 23 cancer cell line, 6 spontaneously immortalized cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0290	HCC1937	Cancer cell line	Female
CVCL_1108	CAL-33	Cancer cell line	Male
CVCL_1576	NCI-H660	Cancer cell line	Male
CVCL_1982	CL-40	Cancer cell line	Female
CVCL_2067	HDQ-P1	Cancer cell line	Female
CVCL_2235	VCaP	Cancer cell line	Male
CVCL_A0BX	VCaP-CR	Cancer cell line	Male
CVCL_A1BP	VCaP AR-V7/pHag	Cancer cell line	Male
CVCL_A5KB	A549-hACE2-TMPRSS2	Cancer cell line	Male
CVCL_A5TF	sciCHO:hACE2:hTMPRSS2	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer