ST14

Summary

ST14 (ST14 transmembrane serine protease matriptase, HGNC:11344) is a protein-coding gene on chromosome 11q24.3, encoding Suppressor of tumorigenicity 14 protein (Q9Y5Y6). Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site.

The protein encoded by this gene is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine 1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scattering factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors. The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis.

Source: NCBI Gene 6768 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 11 (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 307 total — 8 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_021978

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11344
Approved symbol	ST14
Name	ST14 transmembrane serine protease matriptase
Location	11q24.3
Locus type	gene with protein product
Status	Approved
Aliases	SNC19, HAI, MT-SP1, TMPRSS14, CAP3
Ensembl gene	ENSG00000149418
Ensembl biotype	protein_coding
OMIM	606797
Entrez	6768

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 3 retained_intron

ENST00000278742, ENST00000524718, ENST00000530376, ENST00000530532, ENST00000894126, ENST00000894127, ENST00000894128, ENST00000894129, ENST00000894130, ENST00000894131, ENST00000894132, ENST00000894133, ENST00000938964, ENST00000962552

RefSeq mRNA: 1 — MANE Select: NM_021978 NM_021978

CCDS: CCDS8487

Canonical transcript exons

ENST00000278742 — 19 exons

Exon	Start	End
ENSE00000990418	130188114	130188273
ENSE00000990419	130188530	130188657
ENSE00000990421	130188869	130188939
ENSE00000990422	130189739	130189896
ENSE00000990432	130196570	130196700
ENSE00000990433	130197841	130197945
ENSE00000990434	130198308	130198418
ENSE00000990435	130198508	130198621
ENSE00000990436	130198947	130199069
ENSE00000990437	130199951	130200137
ENSE00000990438	130208410	130208684
ENSE00000990439	130209442	130209578
ENSE00000990440	130209662	130210362
ENSE00001334626	130159782	130160060
ENSE00003459405	130190454	130190694
ENSE00003485063	130194640	130194737
ENSE00003493904	130194149	130194288
ENSE00003589538	130190113	130190148
ENSE00003685263	130196339	130196448

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 98.94.

FANTOM5 (CAGE): breadth broad, TPM avg 14.1962 / max 315.4488, expressed in 760 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117629	6.6853	686
117628	6.3445	557
117627	0.7070	330
117630	0.2235	162
117631	0.1423	64
117632	0.0936	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.94	gold quality
nasal cavity epithelium	UBERON:0005384	97.50	gold quality
duodenum	UBERON:0002114	97.41	gold quality
lower esophagus mucosa	UBERON:0035834	97.09	gold quality
ileal mucosa	UBERON:0000331	96.96	gold quality
pharyngeal mucosa	UBERON:0000355	96.37	gold quality
esophagus mucosa	UBERON:0002469	96.30	gold quality
colonic mucosa	UBERON:0000317	96.26	gold quality
jejunal mucosa	UBERON:0000399	96.20	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.13	gold quality
rectum	UBERON:0001052	95.88	gold quality
gingival epithelium	UBERON:0001949	95.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.75	gold quality
pancreatic ductal cell	CL:0002079	95.22	silver quality
gingiva	UBERON:0001828	94.85	gold quality
body of tongue	UBERON:0011876	94.49	gold quality
esophagus squamous epithelium	UBERON:0006920	94.39	gold quality
nasal cavity mucosa	UBERON:0001826	94.31	gold quality
epithelium of esophagus	UBERON:0001976	94.29	gold quality
squamous epithelium	UBERON:0006914	94.25	gold quality
tongue squamous epithelium	UBERON:0006919	94.07	gold quality
pylorus	UBERON:0001166	94.04	gold quality
mouth mucosa	UBERON:0003729	93.99	gold quality
minor salivary gland	UBERON:0001830	93.95	gold quality
tongue	UBERON:0001723	93.94	gold quality
renal medulla	UBERON:0000362	93.71	gold quality
nipple	UBERON:0002030	93.57	gold quality
saliva-secreting gland	UBERON:0001044	93.56	gold quality
cardia of stomach	UBERON:0001162	93.39	gold quality
trachea	UBERON:0003126	93.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	326.81
E-MTAB-10662	yes	91.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1, ZEB1

miRNA regulators (miRDB)

20 targeting ST14, 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-8485	100.00	77.57	4731
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-615-3P	90.62	68.07	69

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• N-terminal catalytic domain of the DNA polymerase epsilon p255 subunit plays role in the G1-S transition and/or S-phase progression of the mitotic cycle. (PMID:22245183)
• Sphingosine 1-phosphate, present in serum-derived lipoproteins, activates matriptase (PMID:11792696)
• Prometastatic effect of N-acetylglucosaminyltransferase V is due to modification and stabilization of active matriptase by adding beta 1-6 GlcNAc branching (PMID:11864986)
• examined the regulation of activation of matriptase in human breast cancer cells (PMID:12498394)
• besides matriptase catalytic activity, matriptase activation requires post-translational modification of the protease, intact noncatalytic domains, and its cognate inhibitor (PMID:12738778)
• Cervical carcinoma cells expressed high levels of TADG-15, suggesting that this protease may play an important role in invasion and metastasis. (PMID:14584072)
• matriptase is downregulated through suppression of activation of receptor-bound pro-urokinase, and leads to inhibition of tumor invasion (PMID:14747469)
• Actin cytoskeletal rearrangement is necessary but not sufficient for S1P-induced activation of matriptase at cell-cell contacts. Matriptase activation to adherens junction assembly and actin cytoskeletal rearrangement may control of matriptase activity. (PMID:15075215)
• SNC19/ST14 could influence on the cell cytoskeletal protein (F-actin) organization and on cell adherence ability to extracellular matrix. (PMID:15200890)
• TADG-15 is associated with early stage ovarian cancer and longer patient survival. (PMID:15611789)
• dysregulated matriptase expression is implicated in malignant epithelial transformation in transgenic mice (PMID:16103220)
• SNC19/ST14 gene overexpression could enhance invasion of colorectal cancer cells in vitro significantly and influence early cell adherence to ECM, but could not change cell movement significantly. (PMID:16237759)
• The expressions of SNC19/matriptase and its inhibitor HAI-1 are decreased in gastrointestinal cancer tissues (PMID:16273651)
• Significantly elevated levels of HAI-1 were detected in 38 patients with prostate cancer before any treatment. (PMID:16353247)
• analysis of ST14 domains and their point and deletion mutants (PMID:16407223)
• Findings demonstrate for the first time that matriptase is overexpressed in many malignant ovarian tumors, and it may be a novel biomarker for diagnosis and treatment of malignant ovarian tumors. (PMID:16439987)
• Matriptase was overexpressed in all subtypes of renal cell carcinomas (RCC), and matriptase scores could distinguish between conventional clear cell RCC, GRCC, and SRCC. (PMID:16501837)
• down-regulation of matriptase expression in THP-1 cells by siRNA reduced the activation of cell-associated pro-uPA and the subsequent rapid initiation of plasminogen activation (PMID:16794252)
• results show that dysregulation of the matriptase/HAI-1 mRNA ratio occurs early during colorectal cancer carcinogenesis (PMID:16820046)
• This review summarizes current knowledge about matriptase, its putative role in tumor initiation and progression, and its potential as a novel target in anti-cancer therapy. (PMID:17131055)
• matriptase-1 plays a vital role in the aggressive nature and progression of prostate cancer (PMID:17228523)
• Mutation in ST14 is associated with autosomal recessive ichthyosis with hypotrichosis (PMID:17273967)
• Autoactivation of matriptase requires protein-protein interactions but not active proteases. (PMID:17344310)
• MT-SP1 mediates extracellular signaling by regulating the local activation of the prometastatic growth factor MSP-1. (PMID:17389401)
• overexpression of MSP, MT-SP1, and MST1R was a strong independent indicator of both metastasis and death in human breast cancer (PMID:17456594)
• reduced activity of a matriptase-prostasin proteolytic cascade is the etiological origin of human ARIH and provides an important mouse model for the exploration of matriptase function in ARIH (PMID:17940283)
• mutation in the ST14 gene is associated with recessive autosomal ichthyosis with hypotrichosis (PMID:17978729)
• MT-SP1 is capable of playing roles in growth factor activation, receptor activation and inactivation, protease activation, and ectodomain shedding (PMID:17981566)
• analysis of the regulation of matriptase and HAI-1 with an emphasis on the molecular mechanisms governing its zymogen activation, inhibition by HAI-1, and ectodomain shedding [review] (PMID:17981575)
• the G827R mutation of matriptase in patients with autosomal recessive ichthyosis with hypotrichosis leads to the expression of an inactive protease (PMID:18263585)
• matriptase/HAI-1 ratios in poorly (1.8 +/- 0.4) and moderately differentiated (1.8 +/- 0.3) were significantly lower than in well differentiated (2.2 +/- 0.2) colorectal adenocarcinomas (PMID:18274158)
• The 2.2 A resolution crystal structure of an Fab antibody inhibitor in complex with the serine protease membrane-type serine protease 1 (MT-SP1/matriptase) reveals the molecular basis of its picomolar potency and specificity. (PMID:18514224)
• Identification in human milk of complexes of matriptase with ATIII, A1AT, or A2AP, provides evidence that the proteolytic activity of matriptase, from cells that express no or low levels of HAI-1, may be controlled by secreted serpins. (PMID:18550704)
• Overexpression of bikunin reduced the gene expression of matriptase, which attenuated in vitro cell invasion. Different metastatic characteristics between PC-3 and PC-J cells suggest that matriptase plays a role in the metastasis of prostate cancer. (PMID:18649735)
• The transient overexpression of MGAT5 significantly enhanced the activity of matriptase and the invasion ability in the LNCaP cells. (PMID:18649738)
• Unlike HAI-1 and matriptase, HAI-2 expression is detected in non-epithelial cells of brain and lymph nodes, suggesting that HAI-2 may also be involved in inhibition of serine proteases other than matriptase (PMID:18713750)
• Alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteases, inhibits the catalytic domain of human recombinant matriptase in vitro. (PMID:18723439)
• increase of matriptase observed for localized prostate cancers, whereas a decrease of matriptase expression is associated with prostate cancer progression. (PMID:18813126)
• Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. (PMID:18843291)
• PAR(2) is a substrate for matriptase in human skin in vivo; Deregulation of these proteins delineates squamous cell carcinoma progression (PMID:19242518)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	st14	ENSDARG00000100088
mus_musculus	St14	ENSMUSG00000031995
rattus_norvegicus	St14	ENSRNOG00000005903
drosophila_melanogaster	Sb	FBGN0003319
drosophila_melanogaster	CG17242	FBGN0250841

Paralogs (17): PRSS22 (ENSG00000005001), PRSS21 (ENSG00000007038), TMPRSS11E (ENSG00000087128), HPN (ENSG00000105707), TMPRSS13 (ENSG00000137747), 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

Suppressor of tumorigenicity 14 protein — Q9Y5Y6 (reviewed: Q9Y5Y6)

Alternative names: Matriptase, Membrane-type serine protease 1, Prostamin, Serine protease 14, Serine protease TADG-15, Tumor-associated differentially-expressed gene 15 protein

All UniProt accessions (1): Q9Y5Y6

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Involved in the terminal differentiation of keratinocytes through prostasin (PRSS8) activation and filaggrin (FLG) processing. Proteolytically cleaves and therefore activates TMPRSS13.

Subunit / interactions. Interacts with CDCP1. May interact with TMEFF1. Interacts with iripin-3, a serine protease inhibitor from Ixodes ricinus saliva. Interacts with iripin-1, a serine protease inhibitor from Ixodes ricinus saliva.

Subcellular location. Membrane.

Disease relevance. Ichthyosis, congenital, autosomal recessive 11 (ARCI11) [MIM:602400] A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (1): NP_068813* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000082	SEA_dom	Domain
IPR000859	CUB_dom	Domain
IPR001254	Trypsin_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR017051	Peptidase_S1A_matripase	Family
IPR018114	TRYPSIN_HIS	Active_site
IPR023415	LDLR_class-A_CS	Conserved_site
IPR033116	TRYPSIN_SER	Active_site
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036364	SEA_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00057, PF00089, PF00431, PF01390

Enzyme classification (BRENDA):

• EC 3.4.21.109 — matriptase (BRENDA: 9 organisms, 282 substrates, 322 inhibitors, 62 Km, 40 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BOC-GLN-ALA-ARG-4-NITROANILIDE	0.024–1	8
METHYLSULFONYL-D-CYCLOHEXYLTYROSYLGLYCYL-ARGININ	0.164–0.228	4
BUTYLOXYCARBONYL-L-GLN-L-ALA-L-ARG-4-NITROANILID	0.159–0.381	3
ALPHAEBETA7 INTEGRIN	0.1–0.111	2
FILAGGRIN	0.03–0.046	2
ILE-PRO-ARG-P-NITROANILIDE	0.256–0.387	2
MATRIPTASE	0.104–0.126	2
METHYLSULFONYL-D-CYCLOHEXYLTYROSYL-GLYCYL-ARGINI	0.17–0.19	2
N-TERT-BUTOXYCARBONYL-GLN-ALA-ARG 7-AMIDO-4-METH	0.0049–0.0335	2
PROTEASE-ACTIVATED RECEPTOR-2	0.142–0.197	2
RQARAVGG	0.018–0.128	2
RQARVVGG	0.104–0.126	2
RRARVVGG	0.0033–0.012	2
SINGLE-CHAIN UROKINASE-TYPE PLASMINOGEN ACTIVATO	0.0035–0.006	2
T-BUTYLOXYCARBONYL-L-GLN-L-ALA-L-ARG-4-METHYL-CO	0.582–0.59	2

UniProt features (72 total): disulfide bond 18, strand 18, domain 8, helix 5, glycosylation site 4, turn 4, active site 3, sequence variant 3, mutagenesis site 3, topological domain 2, chain 1, region of interest 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
3NCL	X-RAY DIFFRACTION	1.19
3P8G	X-RAY DIFFRACTION	1.2
8G1W	X-RAY DIFFRACTION	1.2
1EAX	X-RAY DIFFRACTION	1.3
8G1V	X-RAY DIFFRACTION	1.35
4IS5	X-RAY DIFFRACTION	1.48
3NPS	X-RAY DIFFRACTION	1.5
6T9T	X-RAY DIFFRACTION	1.69
4JZ1	X-RAY DIFFRACTION	1.9
4O9V	X-RAY DIFFRACTION	1.9
4R0I	X-RAY DIFFRACTION	1.9
6N4T	X-RAY DIFFRACTION	1.95
3P8F	X-RAY DIFFRACTION	2
4JYT	X-RAY DIFFRACTION	2
4JZI	X-RAY DIFFRACTION	2
4ISO	X-RAY DIFFRACTION	2.01
2GV6	X-RAY DIFFRACTION	2.1
3SO3	X-RAY DIFFRACTION	2.1
3BN9	X-RAY DIFFRACTION	2.17
2GV7	X-RAY DIFFRACTION	2.2
4O97	X-RAY DIFFRACTION	2.2
4ISL	X-RAY DIFFRACTION	2.29
4ISN	X-RAY DIFFRACTION	2.45
5LYO	X-RAY DIFFRACTION	2.5
1EAW	X-RAY DIFFRACTION	2.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5Y6-F1	81.23	0.36

Antibody-complex structures (SAbDab): 3 — 3BN9, 3NPS, 3SO3

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): 656 (charge relay system); 711 (charge relay system); 805 (charge relay system)

Disulfide bonds (18): 214–244, 340–366, 397–410, 453–464, 459–477, 471–486, 488–501, 496–514, 508–523, 525–537, 532–550, 544–559, 567–579, 574–593, 587–602, 641–657, 776–790, 801–830

Glycosylation sites (4): 109, 302, 485, 772

Mutagenesis-validated functional residues (3):

Position	Phenotype
656	abolishes catalytic activity.
711	abolishes catalytic activity.
805	abolishes catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 273 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, JAEGER_METASTASIS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOCC_CELL_SURFACE, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_EMBRYONIC_PLACENTA_DEVELOPMENT, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT

GO Biological Process (8): neural tube closure (GO:0001843), proteolysis (GO:0006508), protein catabolic process (GO:0030163), keratinocyte differentiation (GO:0030216), epithelial cell morphogenesis involved in placental branching (GO:0060672), complement activation (GO:0006956), epithelial cell differentiation (GO:0030855), animal organ development (GO:0048513)

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 (6): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), basolateral plasma membrane (GO:0016323), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
cellular anatomical structure	2
primary neural tube formation	1
tube closure	1
macromolecule catabolic process	1
epidermal cell differentiation	1
skin development	1
epithelial cell morphogenesis	1
embryonic morphogenesis	1
branching involved in labyrinthine layer morphogenesis	1
epithelial cell differentiation involved in embryonic placenta development	1
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
cell differentiation	1
epithelium development	1
anatomical structure development	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
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
basal plasma membrane	1
plasma membrane region	1

Protein interactions and networks

STRING

1134 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ST14	SPINT1	O43278	929
ST14	SPINK5	Q9NQ38	881
ST14	F8	P00451	869
ST14	SPINT2	O43291	777
ST14	FLG	P20930	739
ST14	FLG2	Q5D862	606
ST14	DSG1	Q02413	605
ST14	ST13	P50502	594
ST14	FURIN	P09958	576
ST14	FMR1	Q06787	561
ST14	SERPINE2	P07093	537
ST14	CDCP1	Q9H5V8	478
ST14	HCFC1	P51610	474
ST14	F2RL1	P55085	449
ST14	MST1R	Q04912	447

IntAct

45 interactions, top by confidence:

A	B	Type	Score
NOTCH2	ST14	psi-mi:“MI:0915”(physical association)	0.550
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
OGFOD3	CLGN	psi-mi:“MI:0914”(association)	0.530
ST14		psi-mi:“MI:0407”(direct interaction)	0.440
ST14	MST1	psi-mi:“MI:0570”(protein cleavage)	0.440
S	ST14	psi-mi:“MI:0570”(protein cleavage)	0.440
ST14	IGFBP7	psi-mi:“MI:0194”(cleavage reaction)	0.440
ST14	AHNAK	psi-mi:“MI:0915”(physical association)	0.400
RGS16	ST14	psi-mi:“MI:0915”(physical association)	0.370
ST14	AKT1	psi-mi:“MI:0915”(physical association)	0.370
APC	ST14	psi-mi:“MI:0915”(physical association)	0.370
ST14	CASP8	psi-mi:“MI:0915”(physical association)	0.370
CDKN2C	ST14	psi-mi:“MI:0915”(physical association)	0.370
ST14	CHEK2	psi-mi:“MI:0915”(physical association)	0.370
PHB1	ST14	psi-mi:“MI:0915”(physical association)	0.370
ST14	RAD51	psi-mi:“MI:0915”(physical association)	0.370
STK11	ST14	psi-mi:“MI:0915”(physical association)	0.370
TGFB1	ST14	psi-mi:“MI:0915”(physical association)	0.370
RAB5A	PSMD14	psi-mi:“MI:0914”(association)	0.350
RAB5A	EIF3CL	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-C	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
P2RX2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LYPD4	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (204): ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Two-hybrid), ST14 (Proximity Label-MS), ST14 (Proximity Label-MS), SPINT1 (Affinity Capture-MS), ST14 (Affinity Capture-MS), ST14 (Proximity Label-MS)

ESM2 similar proteins: A2ARV4, C0HL13, F1RWC3, G3V928, O57409, O60494, O70244, P01130, P01131, P01132, P07522, P20063, P35950, P35951, P35952, P35953, P41413, P46023, P56677, P78504, P98155, P98156, P98157, P98158, P98163, P98164, P98165, P98166, Q04592, Q04833, Q07954, Q0IIH7, Q20176, Q28832, Q63722, Q6X0I2, Q90Y57, Q91ZX7, Q92673, Q92824

Diamond homologs: A0A1S4H5M5, A0A1S4H5S2, A0A6I8TBG6, A0A6J1W8N1, A6MFK7, A6MFK8, B8V7S0, F5HKX0, O18783, O19045, O88947, O97366, P00740, P00741, P00742, P00743, P00745, P00747, P00761, P03951, P06868, P08217, P12545, P14272, P15944, P16293, P16295, P19236, P19540, P20231, P21845, P26262, P27435, P31394, P33587, P35033, P35041, P50342, P50343, P56677

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of cell population proliferation	8	6.9×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	7
Uncertain significance	124
Likely benign	71
Benign	63

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
126420	NM_021978.4(ST14):c.2034del (p.Leu678fs)	Pathogenic
1934660	NM_021978.4(ST14):c.1569C>A (p.Cys523Ter)	Pathogenic
2097966	NM_021978.4(ST14):c.628del (p.Gln210fs)	Pathogenic
2862877	NM_021978.4(ST14):c.1047dup (p.Thr350fs)	Pathogenic
4038	NM_021978.4(ST14):c.2479G>A (p.Gly827Arg)	Pathogenic
4039	NM_021978.4(ST14):c.3G>A (p.Met1Ile)	Pathogenic
4081066	NM_021978.4(ST14):c.598+1G>A	Pathogenic
4715929	NM_021978.4(ST14):c.468G>A (p.Trp156Ter)	Pathogenic
126419	NM_021978.4(ST14):c.2269+1G>A	Likely pathogenic
1325140	NM_021978.4(ST14):c.241+1G>A	Likely pathogenic
3336983	NM_021978.4(ST14):c.2519_2538dup (p.Asp847fs)	Likely pathogenic
3622681	NM_021978.4(ST14):c.1994+1G>A	Likely pathogenic
818079	NM_021978.4(ST14):c.1365dup (p.Gln456fs)	Likely pathogenic
872044	NM_021978.4(ST14):c.238C>T (p.Gln80Ter)	Likely pathogenic
979027	NM_021978.4(ST14):c.1315G>A (p.Gly439Ser)	Likely pathogenic

SpliceAI

2683 predictions. Top by Δscore:

Variant	Effect	Δscore
11:130188109:TGCA:T	acceptor_loss	1.0000
11:130188110:GCA:G	acceptor_loss	1.0000
11:130188111:CAGA:C	acceptor_loss	1.0000
11:130188112:A:AG	acceptor_gain	1.0000
11:130188112:A:C	acceptor_loss	1.0000
11:130188113:G:GA	acceptor_gain	1.0000
11:130188113:GA:G	acceptor_gain	1.0000
11:130188113:GAA:G	acceptor_gain	1.0000
11:130188113:GAAA:G	acceptor_gain	1.0000
11:130188269:GCAGT:G	donor_gain	1.0000
11:130188270:CAGT:C	donor_gain	1.0000
11:130188271:AGTGT:A	donor_loss	1.0000
11:130188272:GT:G	donor_gain	1.0000
11:130188273:TG:T	donor_loss	1.0000
11:130188274:G:GG	donor_gain	1.0000
11:130188517:T:TA	acceptor_gain	1.0000
11:130188518:G:A	acceptor_gain	1.0000
11:130188524:A:AG	acceptor_gain	1.0000
11:130188525:C:G	acceptor_gain	1.0000
11:130188526:A:AG	acceptor_gain	1.0000
11:130188527:C:G	acceptor_gain	1.0000
11:130188527:CA:C	acceptor_loss	1.0000
11:130188528:A:AG	acceptor_gain	1.0000
11:130188528:AGACC:A	acceptor_gain	1.0000
11:130188529:G:GA	acceptor_gain	1.0000
11:130188529:GA:G	acceptor_gain	1.0000
11:130188529:GAC:G	acceptor_gain	1.0000
11:130188529:GACC:G	acceptor_gain	1.0000
11:130188529:GACCG:G	acceptor_gain	1.0000
11:130188624:GTTT:G	donor_gain	1.0000

AlphaMissense

5658 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:130208665:G:C	W750C	1.000
11:130208665:G:T	W750C	1.000
11:130209540:T:A	C790S	0.999
11:130209540:T:C	C790R	0.999
11:130209541:G:C	C790S	0.999
11:130209573:T:A	C801S	0.999
11:130209574:G:A	C801Y	0.999
11:130209574:G:C	C801S	0.999
11:130209575:C:G	C801W	0.999
11:130209743:T:A	C830S	0.999
11:130209744:G:C	C830S	0.999
11:130208663:T:A	W750R	0.998
11:130208663:T:C	W750R	0.998
11:130209542:C:G	C790W	0.998
11:130209573:T:C	C801R	0.998
11:130209574:G:T	C801F	0.998
11:130209733:G:C	W826C	0.998
11:130209733:G:T	W826C	0.998
11:130197915:T:A	C477S	0.997
11:130197916:G:C	C477S	0.997
11:130197917:C:G	C477W	0.997
11:130198388:T:A	C514S	0.997
11:130198389:G:C	C514S	0.997
11:130200025:T:A	W628R	0.997
11:130200025:T:C	W628R	0.997
11:130200027:G:C	W628C	0.997
11:130200027:G:T	W628C	0.997
11:130200034:A:C	S631R	0.997
11:130200036:C:A	S631R	0.997
11:130200036:C:G	S631R	0.997

dbSNP variants (sampled 300 via entrez): RS1000082274 (11:130172066 A>C), RS1000113144 (11:130183470 G>A), RS1000180569 (11:130168025 A>G), RS1000219047 (11:130159489 G>A), RS1000269192 (11:130189592 G>C), RS1000310362 (11:130206272 C>G,T), RS1000315165 (11:130177921 C>T), RS1000345812 (11:130201535 C>T), RS1000392377 (11:130195995 A>G), RS1000434768 (11:130178207 G>T), RS1000443171 (11:130184870 C>G,T), RS1000575038 (11:130166422 AG>A,AGG), RS1000619955 (11:130206484 G>A), RS1000724229 (11:130189235 G>A), RS1000860705 (11:130162197 G>A)

Disease associations

OMIM: gene MIM:606797 | disease phenotypes: MIM:602400

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 11	Strong	Autosomal recessive

Mondo (2): autosomal recessive congenital ichthyosis 11 (MONDO:0011218), ichthyosis (MONDO:0019269)

Orphanet (2): Ichthyosis-hypotrichosis syndrome (Orphanet:91132), Ichthyosis (Orphanet:79354)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000498	Blepharitis
HP:0000613	Photophobia
HP:0000653	Sparse eyelashes
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000989	Pruritus
HP:0001597	Abnormal nail morphology
HP:0002212	Curly hair
HP:0002231	Sparse body hair
HP:0002299	Brittle hair
HP:0003577	Congenital onset
HP:0003777	Pili torti
HP:0007431	Congenital ichthyosiform erythroderma
HP:0007665	Curly eyelashes
HP:0007957	Corneal opacity
HP:0008064	Ichthyosis
HP:0008070	Sparse hair
HP:0011082	Conical primary incisor
HP:0045075	Sparse eyebrow

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008758_15	Pre-treatment viral load in HIV-1 infection	3.000000e-19
GCST009028_61	Adverse response to drug	3.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010125	viral load
EFO:0009658	adverse effect

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
C536273	Ichthyosis with hypotrichosis, autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3018 (SINGLE PROTEIN), CHEMBL3885586 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 53,074 (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
CHEMBL198362	RIVAROXABAN	4	11,497
CHEMBL25105	HEXAMIDINE	4	5,666
CHEMBL55	PENTAMIDINE	4	27,049
CHEMBL273264	NAFAMOSTAT	3	7,063
CHEMBL30044	DIBROMPROPAMIDINE	2	1,799

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
inhibitor 1 [Colombo et al., 2012]	Inhibition	10.96	pKi
I-432	Inhibition	8.7	pKi
N-0385	Inhibition	8.59	pKi
MD5	Inhibition	7.0	pKi
compound 3 [PMID: 23849879]	Inhibition	6.24	pIC50
compound 4d [PMID: 25489658]	Inhibition	5.85	pIC50

Binding affinities (BindingDB)

55 measured of 55 human assays (122 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-2-[[(2R)-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	KI	0.011 nM	US-9365853: Matriptase inhibitors and uses thereof against orthomyxoviridae infections
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(6-amino-2,3,4,5-tetrahydropyridin-3-yl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	0.069 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]pentanediamide	KI	0.088 nM	US-9365853: Matriptase inhibitors and uses thereof against orthomyxoviridae infections
4-[1-[(2S)-2-[[3-(6-amino-2,3,4,5-tetrahydropyridin-3-yl)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	0.49 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
benzyl 1-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidine-4-carboxylate	KI	0.7 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[(2S)-2-[[3-(4-aminobutyl)phenyl]sulfonylamino]-3-[4-(2-aminoethyl)piperidin-1-yl]-3-oxopropyl]benzenecarboximidamide	KI	0.74 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
(2S)-2-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]propanamide	KI	1.4 nM	US-9365853: Matriptase inhibitors and uses thereof against orthomyxoviridae infections
N-[3-[[(2S)-1-[4-(2-aminoethyl)piperidin-1-yl]-3-(3-carbamimidoylphenyl)-1-oxopropan-2-yl]sulfamoyl]phenyl]azetidine-3-carboxamide	KI	1.7 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(4-ethylphenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	2.5 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(6-amino-3-pyridinyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	4.2 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
(3S)-3-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]propanoyl]amino]-4-[[(2R)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	KI	4.6 nM	US-9365853: Matriptase inhibitors and uses thereof against orthomyxoviridae infections
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(3,4-dimethoxyphenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	5.4 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(4-ethoxyphenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	5.4 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(4-methoxyphenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	6 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
benzyl 4-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperazine-1-carboxylate	KI	6.1 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
methyl 4-[1-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]butanoate	KI	6.1 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	6.3 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(4-ethoxyphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	8.1 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
(2S)-N-[(2S)-1-[[(2S)-6-amino-1-(1,3-benzothiazol-2-yl)-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]pentanediamide	KI	9.5 nM	US-9365853: Matriptase inhibitors and uses thereof against orthomyxoviridae infections
4-[1-[(2S)-2-[[3-(6-amino-3-pyridinyl)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	11 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]butanamide	KI	11.8 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-3-oxo-2-[[3-(4-propan-2-yloxyphenyl)phenyl]sulfonylamino]propyl]benzenecarboximidamide	KI	12 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
1-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidine-4-carboxamide	KI	12.1 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(1H-indol-5-yl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	13 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
N-[3-[[(2S)-3-(3-carbamimidoylphenyl)-1-[4-[4-(methylamino)-4-oxobutyl]piperidin-1-yl]-1-oxopropan-2-yl]sulfamoyl]phenyl]azetidine-3-carboxamide	KI	16 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
(2S)-3-amino-N-[3-[[(2S)-1-[4-(2-aminoethyl)piperidin-1-yl]-3-(3-carbamimidoylphenyl)-1-oxopropan-2-yl]sulfamoyl]phenyl]-2-[3-(2-methoxyethoxy)propanoylamino]propanamide	KI	21.8 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(4-propan-2-ylphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	23.5 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(2-oxopiperazin-1-yl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	24 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(4-ethylphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	24.5 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(4-chlorophenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	26 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[(2S)-3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(2-methylpyrimidin-4-yl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	28 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(2-chlorophenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	29 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
1-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidine-3-carboxamide	KI	30.5 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(2-oxopiperidin-1-yl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	31 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-amino-N-[3-[[(2S)-3-(3-carbamimidoylphenyl)-1-oxo-1-piperidin-1-ylpropan-2-yl]sulfamoyl]phenyl]propanamide	KI	32 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-amino-N-[3-[[(2S)-3-(3-carbamimidoylphenyl)-1-oxo-1-piperazin-1-ylpropan-2-yl]sulfamoyl]phenyl]propanamide	KI	36 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
benzyl 4-[(2S)-3-[3-(aminomethyl)phenyl]-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]propanoyl]piperazine-1-carboxylate	KI	44.5 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-3-oxo-2-[(3-pyridin-3-ylphenyl)sulfonylamino]propyl]benzenecarboximidamide	KI	47 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]-N-[2-(2-methoxyethoxy)ethyl]butanamide	KI	54 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-amino-N-[3-[[(2S)-1-[4-(2-aminoethyl)piperidin-1-yl]-3-[3-(aminomethyl)phenyl]-1-oxopropan-2-yl]sulfamoyl]phenyl]propanamide	KI	56 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-3-oxo-2-[(3-pyridin-4-ylphenyl)sulfonylamino]propyl]benzenecarboximidamide	KI	60 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
ethyl 4-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperazine-1-carboxylate	KI	65 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[(2S)-2-[[3-(4-tert-butylphenyl)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	87 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(3-chlorophenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	KI	91 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[1-[3-(3-carbamimidoylphenyl)-2-[[3-(6-oxopyridazin-1-yl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]-N-methylbutanamide	KI	98 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-3-oxo-2-[(3-phenylphenyl)sulfonylamino]propyl]benzenecarboximidamide	KI	100 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
N-[3-[[(2S)-1-[4-(2-aminoethyl)piperidin-1-yl]-3-(3-carbamimidoylphenyl)-1-oxopropan-2-yl]sulfamoyl]phenyl]-3-hydroxypropanamide	KI	117 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
N-[2-[3-[[(2S)-1-[4-(2-aminoethyl)piperidin-1-yl]-3-(3-carbamimidoylphenyl)-1-oxopropan-2-yl]sulfamoyl]anilino]-2-oxoethyl]-3-(2-methoxyethoxy)propanamide	KI	130 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
N-[1-[4-(2-aminoethyl)piperidin-1-yl]-3-[3-(aminomethyl)phenyl]-1-oxopropan-2-yl]-3-(4-methoxyphenyl)benzenesulfonamide	KI	145 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
4-[4-[(2S)-2-[[3-(3-aminopropanoylamino)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperazin-1-yl]-N-[2-(2-methoxyethoxy)ethyl]-4-oxobutanamide	KI	246 nM	US-8569313: Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors

ChEMBL bioactivities

527 potent at pChembl≥5 of 557 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.96	Ki	0.011	nM	CHEMBL2086421
10.96	Ki	0.011	nM	CHEMBL3916317
10.70	Ki	0.02	nM	NAFAMOSTAT
10.21	Ki	0.061	nM	CHEMBL3354674
10.16	Ki	0.069	nM	CHEMBL3655686
10.10	Ki	0.08	nM	CHEMBL3289302
10.10	Ki	0.08	nM	CHEMBL469090
10.06	Ki	0.088	nM	CHEMBL2089123
10.04	Ki	0.092	nM	CHEMBL3352840
9.89	Ki	0.13	nM	CHEMBL4548036
9.89	IC50	0.13	nM	CHEMBL5081575
9.85	Ki	0.14	nM	CHEMBL3354677
9.82	Ki	0.15	nM	CHEMBL3354679
9.80	Ki	0.16	nM	CHEMBL6163291
9.80	Ki	0.16	nM	CHEMBL6163067
9.74	Ki	0.18	nM	CHEMBL3354675
9.66	Ki	0.22	nM	CHEMBL4469801
9.64	Ki	0.23	nM	CHEMBL3354676
9.49	Ki	0.32	nM	CHEMBL3356594
9.44	Ki	0.36	nM	CHEMBL4562668
9.35	Ki	0.45	nM	CHEMBL3354682
9.31	Ki	0.49	nM	CHEMBL3655698
9.30	Ki	0.5	nM	CHEMBL4571215
9.26	Ki	0.55	nM	CHEMBL4454016
9.19	Ki	0.65	nM	CHEMBL4567317
9.16	Ki	0.69	nM	CHEMBL3356592
9.15	Ki	0.7	nM	CHEMBL3655699
9.15	Ki	0.7	nM	CHEMBL5193920
9.14	Ki	0.72	nM	CHEMBL3354678
9.13	Ki	0.74	nM	CHEMBL468270
9.10	Ki	0.8	nM	CHEMBL5207279
9.08	Ki	0.83	nM	CHEMBL3356606
9.05	Ki	0.9	nM	CHEMBL3219101
9.05	Ki	0.89	nM	CHEMBL3354687
9.04	Ki	0.92	nM	CHEMBL239127
9.04	Ki	0.92	nM	CHEMBL3356589
9.04	Ki	0.91	nM	CHEMBL3354681
9.00	Ki	1	nM	CHEMBL3219087
9.00	Ki	1	nM	CHEMBL3289038
9.00	Ki	1	nM	CHEMBL468270
9.00	IC50	1	nM	CHEMBL5086585
9.00	Ki	1	nM	CHEMBL5180135
8.96	Ki	1.1	nM	CHEMBL3356596
8.96	IC50	1.1	nM	CHEMBL4454016
8.96	IC50	1.1	nM	CHEMBL5091091
8.89	Ki	1.3	nM	CHEMBL4587327
8.85	Ki	1.4	nM	CHEMBL2089124
8.85	Ki	1.4	nM	CHEMBL3354686
8.85	Ki	1.4	nM	CHEMBL3951346
8.82	Ki	1.5	nM	CHEMBL379068

PubChem BioAssay actives

502 with measured affinity, of 705 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
(6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate	1171340: Inhibition of matriptase (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	<0.0001	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	682983: Tight binding inhibition of human matriptase 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	<0.0001	uM
(2S)-1-[(2S)-5-amino-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0001	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-5-(diaminomethylideneamino)pentanamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0001	uM
(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]pentanediamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0001	uM
(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]pentanediamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0001	uM
9H-fluoren-9-ylmethyl N-[2-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-2-oxoethyl]carbamate	1575064: Inhibition of recombinant human N-terminal His6-tagged matriptase catalytic domain expressed in Escherichia coli preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0001	uM
(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	1810167: Inhibition of recombinant human N-terminal met-His6-tagged matriptase catalytic domain (Gly596 to Val855 residues) expressed in Escherichia coli using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0001	uM
3-[(2S)-3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(6-amino-2,3,4,5-tetrahydropyridin-3-yl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	410977: Inhibition of matriptase	ki	0.0001	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]pentanediamide	682983: Tight binding inhibition of human matriptase 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	0.0001	uM
3-[(2R)-3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(6-amino-2,3,4,5-tetrahydropyridin-3-yl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	1152290: Inhibition of recombinant matriptase (unknown origin) using Boc-Gln-Ala-Arg-7-amido-4-methyl coumarin hydrobromide	ki	0.0001	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]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]pentanediamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0002	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	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0002	uM
9H-fluoren-9-ylmethyl N-[(2S)-6-amino-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]carbamate	1575064: Inhibition of recombinant human N-terminal His6-tagged matriptase catalytic domain expressed in Escherichia coli preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	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	1171340: Inhibition of matriptase (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0003	uM
(2S)-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]-2-[[(2S)-2,6-diaminohexanoyl]amino]butanediamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0004	uM
9H-fluoren-9-ylmethyl N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]carbamate	1575064: Inhibition of recombinant human N-terminal His6-tagged matriptase catalytic domain expressed in Escherichia coli preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0004	uM
9H-fluoren-9-ylmethyl (2S)-2-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]carbamoyl]pyrrolidine-1-carboxylate	1575064: Inhibition of recombinant human N-terminal His6-tagged matriptase catalytic domain expressed in Escherichia coli preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0005	uM
9H-fluoren-9-ylmethyl N-[(2S)-5-amino-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamate	1575064: Inhibition of recombinant human N-terminal His6-tagged matriptase catalytic domain expressed in Escherichia coli preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0006	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	1575064: Inhibition of recombinant human N-terminal His6-tagged matriptase catalytic domain expressed in Escherichia coli preincubated for 30 mins followed by Boc-QAR-AMC substrate addition and measured for 1 hr by fluorescence assay	ki	0.0006	uM
(2S)-2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-5-(diaminomethylideneamino)pentanamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0007	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	1171340: Inhibition of matriptase (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0007	uM
1-tert-butyl-3-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(3-carbamimidoylphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]urea	1861006: Binding affinity to N-terminal MRGS(His)6GSDDDDK-tagged Matriptase (unknown origin) expressed in Escherichia coli assessed as inhibition constant using Mes-DArg-Pro-Arg-AMC as substrate	ki	0.0007	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	1171340: Inhibition of matriptase (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0008	uM
1-tert-butyl-3-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(4-carbamimidoylphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]urea	1861006: Binding affinity to N-terminal MRGS(His)6GSDDDDK-tagged Matriptase (unknown origin) expressed in Escherichia coli assessed as inhibition constant using Mes-DArg-Pro-Arg-AMC as substrate	ki	0.0008	uM
(2S)-1-[(2S)-4-amino-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-4-oxobutanoyl]-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0009	uM
(2S)-6-amino-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]hexanamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0009	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	1171340: Inhibition of matriptase (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0009	uM
2-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43R,49S)-25-(4-aminobutyl)-49-benzyl-4,19-bis[(2S)-butan-2-yl]-34-[3-(diaminomethylideneamino)propyl]-28-[(1R)-1-hydroxyethyl]-22-(hydroxymethyl)-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-40-yl]acetic acid	108586: Compound was tested for inhibition of Matriptase from human breast cancer cells	ki	0.0009	uM
(3S,6S,14S)-6-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-(2-methylsulfanylethyl)-2,5,8-trioxo-1,4,9-triazacyclotetradecane-14-carboxamide	1810167: Inhibition of recombinant human N-terminal met-His6-tagged matriptase catalytic domain (Gly596 to Val855 residues) expressed in Escherichia coli using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0010	uM
1-[1-[(2S)-2-[[3-[3-(aminomethyl)phenyl]phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]-3-tert-butylurea	1861006: Binding affinity to N-terminal MRGS(His)6GSDDDDK-tagged Matriptase (unknown origin) expressed in Escherichia coli assessed as inhibition constant using Mes-DArg-Pro-Arg-AMC as substrate	ki	0.0010	uM
3-[(2S)-2-[[3-(4-aminobutyl)phenyl]sulfonylamino]-3-[4-(2-aminoethyl)piperidin-1-yl]-3-oxopropyl]benzenecarboximidamide	410977: Inhibition of matriptase	ki	0.0010	uM
(4-aminocyclohexyl) 3,5-bis(4-carbamimidoylphenoxy)benzoate	1152290: Inhibition of recombinant matriptase (unknown origin) using Boc-Gln-Ala-Arg-7-amido-4-methyl coumarin hydrobromide	ki	0.0010	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	1171340: Inhibition of matriptase (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0011	uM
(3S,6S,14S)-6-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-9-methyl-3-(2-methylpropyl)-2,5,8-trioxo-1,4,9-triazacyclotetradecane-14-carboxamide	1810167: Inhibition of recombinant human N-terminal met-His6-tagged matriptase catalytic domain (Gly596 to Val855 residues) expressed in Escherichia coli using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0011	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	1550524: Inhibition of recombinant human matriptase preincubated for 30 mins followed by Boc-QLR-AMC substrate addition by fluorescence assay	ki	0.0013	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]-3-hydroxy-1-oxopropan-2-yl]-4-methylpentanamide	1170922: Inhibition of human recombinant matriptase using Boc-Gln-Ala-Arg-AMC as substrate by microplate reader analysis	ki	0.0014	uM
(2S)-2-amino-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]propanamide	682983: Tight binding inhibition of human matriptase 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	0.0014	uM
3-amino-N-[3-[[(2S)-3-(3-carbamimidoylphenyl)-1-[4-[3-(diaminomethylideneamino)propyl]piperidin-1-yl]-1-oxopropan-2-yl]sulfamoyl]phenyl]propanamide	1798368: Determination of Inhibition Constants from Article 10.1021/jm051272l: “Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase.”	ki	0.0015	uM
3-[(2S)-3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(6-amino-3-pyridinyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	410977: Inhibition of matriptase	ki	0.0016	uM
3-amino-N-[3-[[(2S)-3-(3-carbamimidoylphenyl)-1-[4-[2-(diaminomethylideneamino)ethyl]piperidin-1-yl]-1-oxopropan-2-yl]sulfamoyl]phenyl]propanamide	1798368: Determination of Inhibition Constants from Article 10.1021/jm051272l: “Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase.”	ki	0.0018	uM
(3S,6S,14S)-6-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-(2-methylpropyl)-2,5,8-trioxo-1,4,9-triazacyclotetradecane-14-carboxamide	1810167: Inhibition of recombinant human N-terminal met-His6-tagged matriptase catalytic domain (Gly596 to Val855 residues) expressed in Escherichia coli using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0022	uM
(3S,6S,14S)-6-acetamido-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-3-methyl-2,5,8-trioxo-1,4,9-triazacyclotetradecane-14-carboxamide	1810167: Inhibition of recombinant human N-terminal met-His6-tagged matriptase catalytic domain (Gly596 to Val855 residues) expressed in Escherichia coli using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.0025	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	1550524: Inhibition of recombinant human matriptase preincubated for 30 mins followed by Boc-QLR-AMC substrate addition by fluorescence assay	ki	0.0025	uM
3-[3-[4-(2-aminoethyl)piperidin-1-yl]-2-[[3-(4-ethylphenyl)phenyl]sulfonylamino]-3-oxopropyl]benzenecarboximidamide	410977: Inhibition of matriptase	ki	0.0025	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	2081781: Inhibition of N-terminal Met/6His tagged human recombinant matriptase catalytic domain (Gly596 to Val855 residues) using Boc-QAR-AMC as substrate preincubated for 30 mins followed by substrate addition and measured by fluorescence based analysis	ic50	0.0029	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]-1-oxo-3-phenylpropan-2-yl]hexanamide	1171340: Inhibition of matriptase (unknown origin) using Boc-QAR-AMC as substrate by fluorescence assay	ki	0.0030	uM
1-tert-butyl-3-[1-[(2S)-3-(3-carbamimidoylphenyl)-2-[[3-(2,4-dimethoxyphenyl)phenyl]sulfonylamino]propanoyl]piperidin-4-yl]urea	1861006: Binding affinity to N-terminal MRGS(His)6GSDDDDK-tagged Matriptase (unknown origin) expressed in Escherichia coli assessed as inhibition constant using Mes-DArg-Pro-Arg-AMC as substrate	ki	0.0030	uM
1-[1-[(2S)-2-[[3-(6-amino-3-pyridinyl)phenyl]sulfonylamino]-3-(3-carbamimidoylphenyl)propanoyl]piperidin-4-yl]-3-tert-butylurea	1861006: Binding affinity to N-terminal MRGS(His)6GSDDDDK-tagged Matriptase (unknown origin) expressed in Escherichia coli assessed as inhibition constant using Mes-DArg-Pro-Arg-AMC as substrate	ki	0.0030	uM
N-[3-[[(2S)-1-[4-(2-aminoethyl)piperidin-1-yl]-3-(3-carbamimidoylphenyl)-1-oxopropan-2-yl]sulfamoyl]phenyl]azetidine-3-carboxamide	410977: Inhibition of matriptase	ki	0.0030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression, decreases expression	5
sodium arsenite	decreases expression, increases abundance, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, decreases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	2
aristolochic acid I	increases expression	1
terbufos	increases methylation	1
aflatoxin B2	increases methylation	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Vorinostat	affects cotreatment, increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Calcitriol	increases expression	1
Carcinogens	decreases expression	1
Cisplatin	increases expression	1
Cyclophosphamide	affects cotreatment, affects expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	affects cotreatment, affects expression	1
Fonofos	increases methylation	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Mutagens	decreases expression	1
Parathion	increases methylation	1

ChEMBL screening assays

96 unique, capped per target: 91 binding, 4 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1010203	Binding	Inhibition of matriptase	Modification of the N-terminal sulfonyl residue in 3-amidinophenylalanine-based matriptase inhibitors. — Bioorg Med Chem Lett
CHEMBL4009364	ADMET	Inhibition of recombinant human matriptase (596 to 855 residues) expressed in Escherichia coli using Boc-Gln-Ala-ArgAMC as substrate measured for 1200 mins by fluorescence assay	Modulating the selectivity of matriptase-2 inhibitors with unnatural amino acids. — Eur J Med Chem
CHEMBL868551	Functional	Reduction of matriptase-catalyzed pro-HGF to HGF processing	Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement