TPSB2

Summary

TPSB2 (tryptase beta 2, HGNC:14120) is a protein-coding gene on chromosome 16p13.3, encoding Tryptase beta-2 (P20231). Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type.

Tryptases comprise a family of trypsin-like serine proteases, the peptidase family S1. Tryptases are enzymatically active only as heparin-stabilized tetramers, and they are resistant to all known endogenous proteinase inhibitors. Several tryptase genes are clustered on chromosome 16p13.3. These genes are characterized by several distinct features. They have a highly conserved 3’ UTR and contain tandem repeat sequences at the 5’ flank and 3’ UTR which are thought to play a role in regulation of the mRNA stability. These genes have an intron immediately upstream of the initiator Met codon, which separates the site of transcription initiation from protein coding sequence. This feature is characteristic of tryptases but is unusual in other genes. The alleles of this gene exhibit an unusual amount of sequence variation, such that the alleles were once thought to represent two separate genes, beta II and beta III. Beta tryptases appear to be the main isoenzymes expressed in mast cells, whereas in basophils, alpha-tryptases predominate. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders.

Source: NCBI Gene 64499 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 53 total
• Druggable target: yes
• MANE Select transcript: NM_024164

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14120
Approved symbol	TPSB2
Name	tryptase beta 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197253
Ensembl biotype	protein_coding
OMIM	191081
Entrez	64499

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000606293, ENST00000611196, ENST00000612142, ENST00000711420, ENST00000711421, ENST00000905921, ENST00000905922, ENST00000905923, ENST00000955802, ENST00000955803

RefSeq mRNA: 1 — MANE Select: NM_024164 NM_024164

Canonical transcript exons

ENST00000606293 — 6 exons

Exon	Start	End
ENSE00003473149	1228900	1229063
ENSE00003701673	1229191	1229456
ENSE00003717634	1228336	1228814
ENSE00003717859	1229566	1229737
ENSE00003726960	1230162	1230184
ENSE00003747406	1229891	1229951

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 96.34.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1991 / max 84.3975, expressed in 14 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155824	0.1240	13
155825	0.0751	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	96.34	gold quality
gall bladder	UBERON:0002110	96.28	gold quality
right lung	UBERON:0002167	96.09	gold quality
mucosa of transverse colon	UBERON:0004991	95.52	gold quality
skin of leg	UBERON:0001511	94.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.65	gold quality
lower esophagus	UBERON:0013473	94.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.49	gold quality
body of stomach	UBERON:0001161	94.19	gold quality
urinary bladder	UBERON:0001255	94.11	gold quality
small intestine	UBERON:0002108	94.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.10	gold quality
fundus of stomach	UBERON:0001160	94.06	gold quality
lower esophagus mucosa	UBERON:0035834	93.91	gold quality
zone of skin	UBERON:0000014	93.68	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.86	gold quality
skin of abdomen	UBERON:0001416	92.78	gold quality
esophagus	UBERON:0001043	92.54	gold quality
upper lobe of left lung	UBERON:0008952	92.51	gold quality
transverse colon	UBERON:0001157	92.08	gold quality
right coronary artery	UBERON:0001625	91.67	gold quality
colonic epithelium	UBERON:0000397	90.94	gold quality
adipose tissue	UBERON:0001013	90.92	gold quality
prostate gland	UBERON:0002367	90.88	gold quality
duodenum	UBERON:0002114	90.87	gold quality
esophagus mucosa	UBERON:0002469	90.74	gold quality
minor salivary gland	UBERON:0001830	90.73	gold quality
stomach	UBERON:0000945	89.99	gold quality
vagina	UBERON:0000996	89.34	gold quality
intestine	UBERON:0000160	89.33	gold quality

Single-cell (SCXA)

Detected in 33 experiment(s), a significant marker in 33.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	52869.20
E-MTAB-5061	yes	49313.99
E-CURD-114	yes	47129.44
E-MTAB-6653	yes	46892.96
E-HCAD-1	yes	37366.61
E-MTAB-8142	yes	34983.14
E-CURD-88	yes	34682.71
E-GEOD-139324	yes	30991.65
E-MTAB-8495	yes	30109.07
E-MTAB-10553	yes	29973.05
E-CURD-126	yes	29227.51
E-MTAB-6308	yes	26928.37
E-GEOD-130148	yes	21977.71
E-GEOD-135922	yes	18038.19
E-MTAB-6701	yes	17565.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, MITF, PATZ1, SMAD3

miRNA regulators (miRDB)

24 targeting TPSB2, 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-4283	100.00	66.42	2097
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-510-5P	97.66	65.82	916
HSA-MIR-6805-5P	95.79	64.86	670

Literature-anchored findings (GeneRIF, showing 6)

• Results indicate a key role for heparin in the activation of human betaI- and beta2-tryptase. (PMID:15567416)
• The disease severity and plasma tryptase levels were not affected by the number of alpha or beta tryptase alleles in mastocytosis patients. (PMID:17449330)
• Strong linkage of TPSAB1 and TPSB2 and pairing of deficiency alleles with functional alleles in observed haplotypes protect human subjects from “knockout” genomes and indeed from inheritance of fewer than 2 active alleles. (PMID:19748655)
• These observations indicate that betaII-tryptase activity is post-translationally regulated by an allosteric disulfide bond. (PMID:24142694)
• Allosteric effects of alpha-tryptase protomers on neighboring beta-tryptase protomers likely result in the novel substrate repertoire of alpha/beta-tryptase tetramers that in turn cause some of the clinical features of hereditary alpha-tryptasemia and of other disorders involving mast cells. (PMID:31337736)
• Increase in TPSB2 and TPSD1 Expression in Synovium of Hip Osteoarthritis Patients Who Are Overweight. (PMID:37511292)

Cross-species orthologs

59 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-16l2.17	ENSDARG00000027196
danio_rerio	gzmk	ENSDARG00000028780
danio_rerio	zgc:92313	ENSDARG00000040513
danio_rerio	zgc:112038	ENSDARG00000046140
danio_rerio	si:dkeyp-93a5.2	ENSDARG00000052064
danio_rerio	zgc:165423	ENSDARG00000052905
danio_rerio	prss60.2	ENSDARG00000055644
danio_rerio	zgc:123295	ENSDARG00000056324
danio_rerio	zgc:163079	ENSDARG00000056773
danio_rerio	zgc:153968	ENSDARG00000061858
danio_rerio	si:dkey-32n7.7	ENSDARG00000063444
danio_rerio	prss60.3	ENSDARG00000070710
danio_rerio	prss60.1	ENSDARG00000070713
danio_rerio	si:dkey-32n7.9	ENSDARG00000071841
danio_rerio	gzma	ENSDARG00000090380
danio_rerio	si:dkey-9p24.5	ENSDARG00000094330
danio_rerio		ENSDARG00000101956
danio_rerio		ENSDARG00000101990
mus_musculus	Tpsab1	ENSMUSG00000024173
mus_musculus	Tpsb2	ENSMUSG00000033825
rattus_norvegicus	Tpsb2	ENSRNOG00000018611
rattus_norvegicus	Tpsab1	ENSRNOG00000024181
drosophila_melanogaster	ea	FBGN0000533
drosophila_melanogaster	Ser6	FBGN0011834
drosophila_melanogaster	CG4793	FBGN0028514
drosophila_melanogaster	CG18478	FBGN0028517
drosophila_melanogaster	CG18477	FBGN0028864
drosophila_melanogaster	CG9676	FBGN0030773
drosophila_melanogaster	CG4653	FBGN0030776
drosophila_melanogaster	CG1304	FBGN0031141
drosophila_melanogaster	CG4259	FBGN0031389
drosophila_melanogaster	CG18557	FBGN0031470
drosophila_melanogaster	CG3117	FBGN0031471
drosophila_melanogaster	CG3355	FBGN0031619
drosophila_melanogaster	CG5390	FBGN0032213
drosophila_melanogaster	SPH93	FBGN0032638
drosophila_melanogaster	CG18563	FBGN0032639
drosophila_melanogaster	CG8586	FBGN0033320
drosophila_melanogaster	CG8738	FBGN0033321
drosophila_melanogaster	CG8172	FBGN0033362
drosophila_melanogaster	tpr	FBGN0034661
drosophila_melanogaster	CG9294	FBGN0034666
drosophila_melanogaster	CG14990	FBGN0035496
drosophila_melanogaster	CG6462	FBGN0035663
drosophila_melanogaster	CG4613	FBGN0036427
drosophila_melanogaster	CG9372	FBGN0036891
drosophila_melanogaster	Sp7	FBGN0037515
drosophila_melanogaster	CG11836	FBGN0039272
drosophila_melanogaster	CG9737	FBGN0039758
drosophila_melanogaster	CG9733	FBGN0039759
drosophila_melanogaster	CG11313	FBGN0039798
drosophila_melanogaster	CG18735	FBGN0042098
drosophila_melanogaster	CG31780	FBGN0051780
drosophila_melanogaster	CG31827	FBGN0051827
drosophila_melanogaster	CG32376	FBGN0052376
drosophila_melanogaster	CG32523	FBGN0052523
drosophila_melanogaster	CG40160	FBGN0058160
drosophila_melanogaster	flz	FBGN0286782
caenorhabditis_elegans		WBGENE00006619

Paralogs (3): TPSD1 (ENSG00000095917), TPSG1 (ENSG00000116176), TPSAB1 (ENSG00000172236)

Protein

Protein identifiers

Tryptase beta-2 — P20231 (reviewed: P20231)

Alternative names: Tryptase II

All UniProt accessions (5): A0A087WUI4, A0A087X1U0, A0A140VJT7, A0AAA9YHG7, P20231

UniProt curated annotations — full annotation on UniProt →

Function. Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type. May play a role in innate immunity.

Subunit / interactions. Homotetramer. The active tetramer is converted to inactive monomers at neutral and acidic pH in the absence of heparin. Low concentrations of inactive monomers become active monomers at pH 6.0 in the presence of heparin. When the concentration of active monomers is higher, they convert to active monomers and then to active tetramers. These monomers are active and functionally distinct from the tetrameric enzyme. In contrast to the hidden active sites in the tetrameric form, the active site of the monomeric form is accessible for macromolecular proteins and inhibitors, e.g. fibrinogen which is a substrate for the monomeric but not for the tetrameric form. The monomeric form forms a complex with SERPINB6.

Subcellular location. Secreted.

Polymorphism. There are two alleles; beta-II and beta-III. There are two forms of the beta-III allele, a short and a long form. The short form (also named frameshifted form) is carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. The sequence shown is that of allele beta-III short form.

Similarity. Belongs to the peptidase S1 family. Tryptase subfamily.

RefSeq proteins (1): NP_077078* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.59 — Tryptase (BRENDA: 11 organisms, 228 substrates, 287 inhibitors, 92 Km, 110 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
N-P-TOSYL-GLY-PRO-LYS-P-NITROANILIDE	0.19–4.2	9
D-ILE-PRO-ARG-P-NITROANILIDE	0.4–8.2	8
S-2288	0.32–1.6	5
D-PRO-PHE-ARG-P-NITROANILIDE	1.64–13.5	4
D-VAL-LEU-ARG-P-NITROANILIDE	1.12–3.49	4
MEOCO-NLE-GLY-ARG-P-NITROANILIDE	0.58–1.16	4
Z-D-ARG-GLY-ARG-P-NITROANILIDE	0.04–0.36	4
BZ-ARG-P-NITROANILIDE	0.3–2.36	3
D-PHE-PIP-ARG-P-NITROANILIDE	0.7–0.79	3
GLU-PRO-ARG-P-NITROANILIDE	0.37–0.64	3
TOSYL-GLY-PRO-LYS-P-NITROANILIDE	0.35–0.49	3
AC-PANK-AAC	0.1105–0.1333	2
AC-PRNK-AAC	0.0089–0.0145	2
AC-PRNR-AAC	0.0165–0.0186	2
AC-PRTK-AAC	0.0147–0.0234	2

UniProt features (46 total): strand 18, helix 5, disulfide bond 4, turn 4, sequence variant 3, sequence conflict 3, active site 3, signal peptide 1, propeptide 1, chain 1, domain 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9QFU	X-RAY DIFFRACTION	1.98
2FPZ	X-RAY DIFFRACTION	2
4A6L	X-RAY DIFFRACTION	2.05
9QFV	X-RAY DIFFRACTION	2.06
3V7T	X-RAY DIFFRACTION	2.09
2BM2	X-RAY DIFFRACTION	2.2
2FWW	X-RAY DIFFRACTION	2.25
2FS9	X-RAY DIFFRACTION	2.3
2ZA5	X-RAY DIFFRACTION	2.3
2GDD	X-RAY DIFFRACTION	2.35
2FS8	X-RAY DIFFRACTION	2.5
2FXR	X-RAY DIFFRACTION	2.5
1A0L	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20231-F1	91.79	0.87

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): 74 (charge relay system); 121 (charge relay system); 224 (charge relay system)

Post-translational modifications (1): 97

Disulfide bonds (4): 155–230, 188–211, 220–248, 59–75

Glycosylation sites (1): 233

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 63 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, MARTINEZ_RB1_TARGETS_DN, MARTINEZ_RB1_AND_TP53_TARGETS_UP, GOBP_PROTEOLYSIS, NIKOLSKY_BREAST_CANCER_16P13_AMPLICON, GOMF_PEPTIDASE_ACTIVITY, YOSHIMURA_MAPK8_TARGETS_UP, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_UP, MCBRYAN_PUBERTAL_BREAST_6_7WK_UP, GOCC_PEPTIDASE_COMPLEX, GSE13522_CTRL_VS_T_CRUZI_BRAZIL_STRAIN_INF_SKIN_DN, GOCC_EXTERNAL_ENCAPSULATING_STRUCTURE, ZNF329_TARGET_GENES

GO Biological Process (1): proteolysis (GO:0006508)

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 (3): obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic 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
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TPSB2	TUBB4A	psi-mi:“MI:0914”(association)	0.530
NCK1	TPSB2	psi-mi:“MI:0915”(physical association)	0.400
PIK3R1	TPSB2	psi-mi:“MI:0915”(physical association)	0.400
TPSB2	rep	psi-mi:“MI:0915”(physical association)	0.370
TPSB2	XRCC3	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): TPSAB1 (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), PRKD2 (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), TUBB4A (Affinity Capture-MS), GALNS (Affinity Capture-MS), TUBB2A (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), XRCC3 (Affinity Capture-MS), PC (Affinity Capture-MS), SEL1L (Affinity Capture-MS), TUBB2B (Affinity Capture-MS), TUBA1C (Affinity Capture-MS), TPSAB1 (Negative Genetic)

ESM2 similar proteins: A1L453, A2VE36, A6NIE9, A8MTI9, E5RG02, O35453, O70169, P08709, P20231, P21845, P50343, P83748, Q14B25, Q14BX2, Q15661, Q16651, Q2F9P2, Q2F9P4, Q2UVH8, Q3UKY7, Q3V0Q7, Q402U7, Q571E5, Q5FBW1, Q5FBW2, Q5M8S2, Q6AXZ6, Q6BEA2, Q6IE62, Q6IE63, Q6UWB4, Q76HL1, Q7RTY5, Q7Z410, Q7Z5A4, Q8BJR6, Q8K4I7, Q8VIF2, Q920S2, Q99MS4

Diamond homologs: A0A182C2Z2, B8V7S0, O08762, O60235, P00747, P00760, P00762, P00765, P00766, P00767, P00774, P03951, P03952, P04070, P04813, P05981, P06867, P06871, P06872, P07146, P07338, P07477, P08217, P08426, P08519, P12545, P14272, P15944, P17538, P19799, P20231, P20918, P26262, P27435, P29786, P35033, P40313, P47796, P50342, P56677

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

924 predictions. Top by Δscore:

Variant	Effect	Δscore
16:1228894:GCCCA:G	donor_loss	1.0000
16:1228895:CCCA:C	donor_loss	1.0000
16:1228896:CCAC:C	donor_loss	1.0000
16:1228897:CAC:C	donor_loss	1.0000
16:1228898:A:T	donor_loss	1.0000
16:1228899:C:CA	donor_loss	1.0000
16:1228914:T:TA	donor_gain	1.0000
16:1229064:C:CC	acceptor_gain	1.0000
16:1228813:CCCTG:C	acceptor_loss	0.9900
16:1228816:T:A	acceptor_loss	0.9900
16:1228911:C:A	donor_gain	0.9900
16:1229060:CGCT:C	acceptor_gain	0.9900
16:1229061:GCT:G	acceptor_gain	0.9900
16:1229062:CT:C	acceptor_gain	0.9900
16:1229062:CTC:C	acceptor_gain	0.9900
16:1229063:TCT:T	acceptor_gain	0.9900
16:1229064:C:CG	acceptor_loss	0.9900
16:1229065:T:A	acceptor_loss	0.9900
16:1229190:CCAT:C	donor_gain	0.9900
16:1229225:G:C	donor_gain	0.9900
16:1229234:C:A	donor_gain	0.9900
16:1229307:T:TA	donor_gain	0.9900
16:1229452:CGTCC:C	acceptor_gain	0.9900
16:1229885:ACT:A	donor_loss	0.9900
16:1229886:CT:C	donor_loss	0.9900
16:1229887:T:TA	donor_loss	0.9900
16:1229889:A:AC	donor_gain	0.9900
16:1229889:A:AT	donor_loss	0.9900
16:1229890:C:CA	donor_loss	0.9900
16:1229890:C:CC	donor_gain	0.9900

AlphaMissense

1771 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1003156276 (16:1230347 C>T), RS1005083949 (16:1231552 C>T), RS1007236882 (16:1228387 C>A,T), RS1007545361 (16:1228890 C>T), RS1008965773 (16:1230684 G>A,T), RS1009169970 (16:1230611 C>T), RS1011689783 (16:1228169 G>A), RS1012687654 (16:1230395 C>T), RS1012761346 (16:1231805 C>T), RS1013153561 (16:1230588 T>C,G), RS1017895670 (16:1230697 G>A), RS1018631763 (16:1228925 C>G), RS1020298072 (16:1228006 A>C,G), RS1021249947 (16:1230138 G>C), RS1021302405 (16:1230396 A>G)

Disease associations

OMIM: gene MIM:191081 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_1107	Blood protein levels	1.000000e-162
GCST006585_26	Blood protein levels	9.000000e-114

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523196 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

20 measured of 23 human assays (44 total across all organisms); most potent 20 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(2R)-N-[(1S)-1-{[6-amino-1-(1,3-benzothiazol-2-yl)-1-oxohexan-2-yl]carbamoyl}-2-phenylethyl]-3-phenyl-2-(phenylmethane)sulfonamidopropanamide	KI	23 nM
2-(1H-benzimidazol-2-ylcarbonyl)-1H-benzimidazole-6-carboximidamide	KI	101 nM
2-pyridin-2-yl-1H-benzimidazole-6-carboximidamide	KI	721 nM
2-isoquinolin-3-yl-1H-benzimidazole-6-carboximidamide	KI	1850 nM
2-(1H-1,3-benzodiazol-2-ylmethyl)-1H-1,3-benzodiazole-6-carboximidamide	KI	2310 nM
2-(pyridin-2-ylmethyl)-1H-1,3-benzodiazole-6-carboximidamide	KI	10500 nM
2-{5-[amino(iminiumyl)methyl]-6-fluoro-1H-1,3-benzodiazol-2-yl}-6-phenylbenzen-1-olate	KI	12000 nM
2-(1H-imidazol-2-ylmethyl)-1H-1,3-benzodiazole-6-carboximidamide	KI	15300 nM
(2S)-N-[3-(2-amino-1H-1,3-benzodiazol-5-yl)-1-(1,3-benzothiazol-2-yl)-1-oxopropan-2-yl]-3-phenyl-2-[(2R)-3-phenyl-2-(phenylmethane)sulfonamidopropanamido]propanamide	KI	18000 nM
2-quinolin-8-yl-1H-benzimidazole-6-carboximidamide	KI	20100 nM
Benzo[b]thiophene-2-carboxamidine	KI	21000 nM
CA-01	KI	30000 nM
N-[3-(2-amino-1H-1,3-benzodiazol-5-yl)-1-(1,3-benzothiazol-2-yl)-1-oxopropan-2-yl]acetamide	KI	31000 nM
2-(isoquinolin-1-yl)-1H-1,3-benzodiazole-6-carboximidamide	KI	31000 nM
2-{5-[amino(iminiumyl)methyl]-6-fluoro-1H-1,3-benzodiazol-2-yl}-6-{[(1S,2S)-2-methylcyclohexyl]oxy}benzen-1-olate	KI	32000 nM
[amino({5-[(3-hydroxynaphthalene-2-)amido]pyridin-2-yl}amino)methylidene]azanium	KI	70000 nM
3-(2-amino-1H-1,3-benzodiazol-5-yl)-1-(1,3-benzothiazol-2-yl)propan-1-one	KI	94000 nM
Benzamidine	KI	110000 nM
[amino(thieno[2,3-b]pyridin-2-yl)methylidene]azanium	KI	360000 nM
JMC524454 Compound 5	KI	1.8e+06 nM

ChEMBL bioactivities

8 potent at pChembl≥5 of 10 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.46	IC50	350	nM	CHEMBL4468000
5.64	IC50	2300	nM	CHEMBL4475961
5.48	IC50	3300	nM	CHEMBL4535197
5.48	IC50	3300	nM	CHEMBL4584532
5.44	IC50	3600	nM	CHEMBL4483713
5.43	IC50	3700	nM	CHEMBL4246585
5.19	IC50	6500	nM	CHEMBL4548070
5.06	IC50	8700	nM	CHEMBL4463116

PubChem BioAssay actives

33 with measured affinity, of 75 total; 31 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
ethyl N-[(2S)-6-amino-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxohexan-2-yl]carbamate	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.0030	uM
N-[(2S)-6-amino-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxohexan-2-yl]-3,4-difluorobenzamide	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.0040	uM
2-[(6-carbamimidoyl-1H-benzimidazol-2-yl)methyl]-3H-benzimidazole-5-carboximidamide	1797494: Enzyme Inhibition Assay from Article 10.1038/35422: “Design of potent selective zinc-mediated serine protease inhibitors.”	ki	0.0050	uM
(2R)-1-acetyl-N-[(2S)-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxo-4-pyrrolidin-3-ylbutan-2-yl]pyrrolidine-2-carboxamide	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.0060	uM
N-[(2S)-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxo-4-pyrrolidin-3-ylbutan-2-yl]-3,4-difluorobenzamide	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.0210	uM
(2S)-N-[6-amino-1-(1,3-benzothiazol-2-yl)-1-oxohexan-2-yl]-2-[[(2R)-2-(benzylsulfonylamino)-3-phenylpropanoyl]amino]-3-phenylpropanamide	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.0230	uM
prop-2-enyl N-[(2S)-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxo-4-pyrrolidin-3-ylbutan-2-yl]carbamate	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.0250	uM
2-(1H-benzimidazole-2-carbonyl)-3H-benzimidazole-5-carboximidamide	1797494: Enzyme Inhibition Assay from Article 10.1038/35422: “Design of potent selective zinc-mediated serine protease inhibitors.”	ki	0.0500	uM
2-(1H-benzimidazol-2-ylmethyl)-3H-benzimidazole-5-carboximidamide	1797494: Enzyme Inhibition Assay from Article 10.1038/35422: “Design of potent selective zinc-mediated serine protease inhibitors.”	ki	0.0695	uM
methyl N-[(2S)-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxo-4-pyrrolidin-3-ylbutan-2-yl]carbamate	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.1300	uM
2-(pyridin-2-ylmethyl)-3H-benzimidazole-5-carboximidamide	1797494: Enzyme Inhibition Assay from Article 10.1038/35422: “Design of potent selective zinc-mediated serine protease inhibitors.”	ki	0.3100	uM
2-[2-[[3-[3-(aminomethyl)phenyl]phenyl]methoxy]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	0.3500	uM
N-[(2S)-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxo-4-piperidin-4-ylbutan-2-yl]-3,4-difluorobenzamide	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.4300	uM
N-[(2S)-4-(azetidin-3-yl)-1-[5-[[4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenyl]methyl]-1,2,4-oxadiazol-3-yl]-1-oxobutan-2-yl]-3,4-difluorobenzamide	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	0.5900	uM
N-[6-(diaminomethylideneamino)pyridin-1-ium-3-yl]-3-hydroxynaphthalene-2-carboxamide	1797227: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1016/j.jmb.2004.09.032: “Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).”	ki	0.8700	uM
[amino-(4-iodo-1-benzothiophen-2-yl)methylidene]azanium	1797179: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1016/S1074-5521(00)00104-6: “Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator.”	ki	1.5000	uM
2-pyridin-2-yl-3H-benzimidazole-5-carboximidamide	1797494: Enzyme Inhibition Assay from Article 10.1038/35422: “Design of potent selective zinc-mediated serine protease inhibitors.”	ki	1.6000	uM
2-(1H-imidazol-2-ylmethyl)-3H-benzimidazole-5-carboximidamide	1797494: Enzyme Inhibition Assay from Article 10.1038/35422: “Design of potent selective zinc-mediated serine protease inhibitors.”	ki	1.6500	uM
diaminomethylidene-[4-[(3-hydroxynaphthalene-2-carbonyl)amino]phenyl]azanium	1797227: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1016/j.jmb.2004.09.032: “Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).”	ki	2.0000	uM
2-[2-[[3-[3-(aminomethyl)phenyl]benzoyl]amino]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	2.3000	uM
6-fluoro-2-[2-hydroxy-3-[(1S,2S)-2-methylcyclohexyl]oxyphenyl]-1H-benzimidazole-5-carboximidamide	1797227: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1016/j.jmb.2004.09.032: “Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).”	ki	2.5000	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(2-hydroxypropan-2-yl)phenyl]methoxy]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	3.3000	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-bromophenyl]methoxy]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	3.3000	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(methoxymethyl)phenyl]methoxy]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	3.6000	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(hydroxymethyl)phenyl]methoxy]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	3.7000	uM
6-fluoro-2-(2-hydroxy-3-phenylphenyl)-1H-benzimidazole-5-carboximidamide	1797227: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1016/j.jmb.2004.09.032: “Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).”	ki	4.7000	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]phenyl]methoxy]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	6.5000	uM
benzyl N-[(2S)-6-amino-1-(1,3-benzothiazol-2-yl)-1-oxohexan-2-yl]carbamate	1797191: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1021/bi060173m: “Structure-guided design of peptide-based tryptase inhibitors.”	ki	7.3000	uM
2-[2-[[3-[3-[(1S)-1-amino-2-hydroxyethyl]phenyl]-5-(propan-2-ylamino)phenyl]methoxy]phenyl]acetic acid	1595856: Inhibition of tryptase-beta2 (unknown origin)	ic50	8.7000	uM
2-isoquinolin-1-yl-3H-benzimidazole-5-carboximidamide	1797494: Enzyme Inhibition Assay from Article 10.1038/35422: “Design of potent selective zinc-mediated serine protease inhibitors.”	ki	8.8000	uM
[amino(1-benzothiophen-2-yl)methylidene]azanium	1797179: Enzyme Assay and Determination of the Inhibition Constants from Article 10.1016/S1074-5521(00)00104-6: “Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator.”	ki	9.9000	uM

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
4-phenylenediamine	increases secretion, affects reaction	1
CGP 52608	affects binding, increases reaction	1
proadrenomedullin (9-20)	increases secretion	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation	1
p-Methoxy-N-methylphenethylamine	increases secretion	1
Latex	decreases expression	1
Methotrexate	increases expression	1
Valproic Acid	increases methylation	1
Isotretinoin	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4341495	Binding	Inhibition of tryptase b2 (unknown origin) at 10 uM relative to control	Peptide-based covalent inhibitors of MALT1 paracaspase. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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