KLKB1

Summary

KLKB1 (kallikrein B1, HGNC:6371) is a protein-coding gene on chromosome 4q35.2, encoding Plasma kallikrein (P03952). Participates in the surface-dependent activation of blood coagulation.

This gene encodes a glycoprotein that participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation. The encoded preproprotein present in plasma as a non-covalent complex with high molecular weight kininogen undergoes proteolytic processing mediated by activated coagulation factor XII to generate a disulfide-linked, heterodimeric serine protease comprised of heavy and light chains. Certain mutations in this gene cause prekallikrein deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 3818 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited prekallikrein deficiency (Definitive, ClinGen)
• GWAS associations: 51
• Clinical variants (ClinVar): 231 total — 5 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 10 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000892

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6371
Approved symbol	KLKB1
Name	kallikrein B1
Location	4q35.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164344
Ensembl biotype	protein_coding
OMIM	229000
Entrez	3818

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 retained_intron

ENST00000264690, ENST00000428196, ENST00000446598, ENST00000467271, ENST00000511406, ENST00000513864, ENST00000860321, ENST00000860322, ENST00000860323, ENST00000860324

RefSeq mRNA: 3 — MANE Select: NM_000892 NM_000892, NM_001318394, NM_001318396

CCDS: CCDS34120, CCDS82982

Canonical transcript exons

ENST00000264690 — 15 exons

Exon	Start	End
ENSE00001612709	186258021	186258471
ENSE00001723972	186227507	186227587
ENSE00003668787	186228195	186228253
ENSE00004472110	186250243	186250402
ENSE00004473748	186251219	186251328
ENSE00004473753	186254588	186254763
ENSE00004473792	186252017	186252185
ENSE00004473859	186257226	186257365
ENSE00004473891	186251749	186251861
ENSE00004473928	186238256	186238365
ENSE00004473944	186255992	186256087
ENSE00004473956	186251487	186251649
ENSE00004473960	186233952	186234058
ENSE00004474132	186236781	186236940
ENSE00004474215	186232127	186232289

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 96.73.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7364 / max 2183.5834, expressed in 22 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177180	1.7364	22
50905	0.5275	17
50906	0.0606	9
177179	0.0046	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.73	gold quality
liver	UBERON:0002107	96.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.91	gold quality
tendon of biceps brachii	UBERON:0008188	82.20	gold quality
body of pancreas	UBERON:0001150	81.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.97	gold quality
epithelial cell of pancreas	CL:0000083	78.90	gold quality
metanephros cortex	UBERON:0010533	78.58	gold quality
jejunal mucosa	UBERON:0000399	78.15	gold quality
pancreatic ductal cell	CL:0002079	77.56	silver quality
pancreas	UBERON:0001264	77.11	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	76.45	gold quality
middle temporal gyrus	UBERON:0002771	76.26	silver quality
choroid plexus epithelium	UBERON:0003911	76.25	gold quality
buccal mucosa cell	CL:0002336	75.91	gold quality
right uterine tube	UBERON:0001302	75.18	gold quality
nucleus accumbens	UBERON:0001882	74.36	gold quality
caudate nucleus	UBERON:0001873	74.35	gold quality
Brodmann (1909) area 23	UBERON:0013554	73.81	gold quality
duodenum	UBERON:0002114	73.56	gold quality
adult mammalian kidney	UBERON:0000082	73.47	gold quality
putamen	UBERON:0001874	73.37	gold quality
adenohypophysis	UBERON:0002196	73.36	gold quality
islet of Langerhans	UBERON:0000006	72.64	gold quality
pituitary gland	UBERON:0000007	72.64	gold quality
primary visual cortex	UBERON:0002436	72.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.50	gold quality
gall bladder	UBERON:0002110	72.49	gold quality
lower esophagus	UBERON:0013473	72.45	gold quality
right coronary artery	UBERON:0001625	72.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

7 targeting KLKB1, 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-1251-3P	99.64	67.21	1408
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-1265	98.36	66.46	598
HSA-MIR-4683	95.29	65.98	631

Literature-anchored findings (GeneRIF, showing 36)

• plasma kallikrein and FXIa activate pro-HGF in vitro (PMID:12372819)
• the effect of kininogen degradation by human neutrophil elastase (HNE) on kinin generation by tissue and plasma kallikreins. (PMID:12887060)
• prekallikrein preferential binding to endothelial cells contributes to their anticoagulant nature (PMID:12944405)
• Crystallization and x-ray crystal structure determination have yielded the first three-dimensional views of the catalytic domain of plasma kallikrein (PMID:16199530)
• Our findings suggested that common genetic variation in the KLKB1 gene might contribute to the risk of hypertension in the northern Han Chinese population. (PMID:17318641)
• study demonstrates by immunohistochemistry that plasma kallikrein (PK) is localised in cells of different embryologically derived human tissues (PMID:17696780)
• three-dimensional structural data for prekallikrein (PK); interaction between PK and high-molecular-weight kininogen is mediated by two discrete surfaces formed by the PK A1, A2 and A4 domains with charge likely to be a critical component of the binding (PMID:17922805)
• Kallikrein can directly activate prothrombin; there is a shortcut in the intrinsic hemostasis system that generates catalytic amounts of thrombin without following the known intrinsic clotting pathway (PMID:18160576)
• Kallikrein is responsible for the cleavage of factor H. (PMID:18413232)
• extensive cytoplasmic expression of tissue prokallikrein and plasma prekallikrein was observed, which was similar in small cell and non-small cell lung tumours; however, nuclear labelling for the kallikreins was absent or limited (PMID:18713009)
• prekallikrein is an enzyme that can cleave high-molecular-weight kininogen to release bradykinin, and this reaction is inhibited by C1 inhibitor. (PMID:19342086)
• NPY3-35 is a new peptide generated by plasma kallikrein (PMID:19620246)
• Case Report: Fresh frozen plasma transfusion before coronary artery bypass corrects prekallikrein deficiency. (PMID:20135073)
• Investigate the relationship between circulating PK levels in children with metabolic syndrome and CVD risk factors because PK may be involved in the progression of the disease state. (PMID:20725119)
• The acquisition of an active site in prekallikrein as a result of binding to high-molecular-weight kininogen (HK) is a new concept for bradykinin formation and might be relevant in the pathogenesis of hereditary angiodema types I and II. (PMID:23672780)
• FXI may have a role in risk of ischemic stroke, but not myocardial infarct; FXII and prekallikrein may not have a role in either (PMID:24977287)
• Prekallikrein deficiency in a family is due to a new mutation (Arg541Gln) in exon 14. (PMID:25075649)
• PRCP1 interacts with plasma kallikrein (PK) at multiple sites for PK activation. (PMID:25324000)
• 2 genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS. (PMID:25477429)
• KLKB1 mRNA expression is a putative molecular biomarker in chronic lymphocytic leukemia. (PMID:25891023)
• these data indicate that KLKB1 induces inflammatory reactions in human dental tissues via protease-activated receptor 1 (PMID:26566265)
• Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. (PMID:26969407)
• von Willebrand factor activity and concentration of prekallikrein may both be of importance regarding the evolution of thrombus in abdominal aortic aneurysm and possible biomarkers for aneurysm growth. (PMID:27581227)
• High molecular weight kinin functions as a cofactor for PK activation in the presence of nucleic acids in a manner consistent with classic models of contact activation. (PMID:28124063)
• Plasma kallikrein (PLK)-dependent transforming growth factor-beta (TGF-beta) activation could be detected in isolated pancreatic stellate cells (PSCs) from chronic pancreatitis (CP) and pancreatic cancer. (PMID:28187111)
• genetic polymorphism is associated with C1 Inhibitor deficiency angioedema age of onset in European families (PMID:29130992)
• We further define the interactions of keratinocyte PKK with TP63 and NF-kappaB signaling, highlighting the importance of this protein as a tumor suppressor in skin squamous cell carcinoma development. (PMID:29186361)
• Kallikrein cleaves central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by C3 convertase. Kallikrein-generated C3b forms C3 convertases, which trigger C3 amplification loop. Kallikrein-generated C3 convertases are inhibited by factor H; suggesting activation of the contact system locally enhances complement activation on cell surfaces. (PMID:29237166)
• These results highlight a novel and specific approach to target PKK for the treatment of HAE and other diseases involving contact system activation and overproduction of bradykinin. (PMID:30817230)
• Plasma high molecular weight kininogen and prekallikrein concentrations were not associated with incident cardiovascular disease. (PMID:31473403)
• Severe plasma prekallikrein deficiency: Clinical characteristics, novel KLKB1 mutations, and estimated prevalence. (PMID:32202057)
• c.451dupT in KLKB1 is common in Nigerians, confirming a higher prevalence of severe prekallikrein deficiency in Africans compared to Europeans. (PMID:33073460)
• Kallikrein augments the anticoagulant function of the protein C system in thrombin generation. (PMID:34532976)
• [Matrix metalloproteinase 14 and plasma kallikrein 1 may be potential biomarkers in the diagnosis and treatment of sepsis: a proteomics and bioinformatics analysis]. (PMID:36100402)
• KLKB1 and CLSTN2 are associated with HDL-mediated cholesterol efflux capacity in a genome-wide association study. (PMID:36812656)
• CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema. (PMID:38294975)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	f9a	ENSDARG00000010097
danio_rerio	habp2	ENSDARG00000057498
mus_musculus	Klkb1	ENSMUSG00000109764
rattus_norvegicus	Klkb1	ENSRNOG00000014118
drosophila_melanogaster	CG31266	FBGN0051266
drosophila_melanogaster	CG31267	FBGN0051267

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), C1R (ENSG00000159403), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Protein

Protein identifiers

Plasma kallikrein — P03952 (reviewed: P03952)

Alternative names: Fletcher factor, Kininogenin, Plasma prekallikrein

All UniProt accessions (4): C9J075, C9JCT1, E9PBC5, P03952

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the surface-dependent activation of blood coagulation. Activates, in a reciprocal reaction, coagulation factor XII/F12 after binding to negatively charged surfaces. Releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin.

Subunit / interactions. Forms a heterodimer with SERPINA5. The zymogen is activated by factor XIIa, which cleaves the molecule into a light chain, which contains the active site, and a heavy chain, which associates with HMW kininogen. These chains are linked by one or more disulfide bonds. 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. Secreted.

Tissue specificity. Found in plasma (at protein level).

Disease relevance. Prekallikrein deficiency (PKKD) [MIM:612423] An autosomal recessive condition characterized by a clotting defect due to prolongation of activated partial thromboplastin time. Affected individuals are clinically asymptomatic. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by SERPINA5.

Similarity. Belongs to the peptidase S1 family. Plasma kallikrein subfamily.

RefSeq proteins (3): NP_000883, NP_001305323, NP_001305325 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000177	Apple	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR003609	Pan_app	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00024, PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.34 — plasma kallikrein (BRENDA: 20 organisms, 187 substrates, 209 inhibitors, 33 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
D-BUTYL-CYCLOHEXYLALANINE-ARGININE-4-NITROANILID	0.091–0.117	3
NALPHA-BENZOYL-L-ARGININE ETHYL ESTER	0.0136–0.0962	2
NALPHA-TOLUENESULFONYL-L-ARGININE METHYL ESTER	0.0016–0.136	2
2-AMINOBENZOIC ACID-GLY-PHE-SER-PRO-PHE-ARG-SER-	0.0049	1
ACETYL-PHE-ARG-4-NITROANILIDE	0.736	1
APELIN-17	0.097	1
D-VAL-LEU-ARG-4-NITROANILIDE	3	1
FACTOR XII	0.0024	1
H-D-PRO-PHE-ARG-4-NITROANILIDE	0.269	1
HIGH-MOLECULAR-WEIGHT KININOGEN	0.0008	1
KININOGEN	0.0008	1
N-ACETYL-PHE-ARG-4-NITROANILIDE	1.81	1
N-BENZOYL-PHE-VAL-ARG-4-NITROANILIDE	1.7	1
NEUROPEPTIDE Y3-36	0.0281	1
O-AMINOBENZOYL-FSAPMKRLTLGNTTQ-N-(2,4-DINITROPHE	0.0045	1

UniProt features (109 total): strand 39, helix 19, disulfide bond 18, sequence variant 14, glycosylation site 5, domain 5, active site 3, turn 3, chain 2, signal peptide 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
6I44	X-RAY DIFFRACTION	1.36
2ANY	X-RAY DIFFRACTION	1.4
5TJX	X-RAY DIFFRACTION	1.41
6T7P	X-RAY DIFFRACTION	1.42
5F8Z	X-RAY DIFFRACTION	1.5
5F8X	X-RAY DIFFRACTION	1.55
10LR	X-RAY DIFFRACTION	1.58
10MW	X-RAY DIFFRACTION	1.62
10MV	X-RAY DIFFRACTION	1.66
6O1S	X-RAY DIFFRACTION	1.7
10QS	X-RAY DIFFRACTION	1.73
5F8T	X-RAY DIFFRACTION	1.75
9VWT	X-RAY DIFFRACTION	1.77
10KZ	X-RAY DIFFRACTION	1.78
8A3Q	X-RAY DIFFRACTION	1.8
2ANW	X-RAY DIFFRACTION	1.85
7N7X	X-RAY DIFFRACTION	2.1
4OGY	X-RAY DIFFRACTION	2.1
6O1G	X-RAY DIFFRACTION	2.2
7QOX	X-RAY DIFFRACTION	2.32
4OGX	X-RAY DIFFRACTION	2.4
8FGX	ELECTRON MICROSCOPY	2.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03952-F1	88.27	0.70

Antibody-complex structures (SAbDab): 3 — 4OGX, 4OGY, 8FGX

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): 578 (charge relay system); 434 (charge relay system); 483 (charge relay system)

Disulfide bonds (18): 21–104, 47–77, 51–57, 111–194, 137–166, 141–147, 201–284, 227–256, 231–237, 292–375, 318–347, 322–328, 340–345, 383–503, 419–435, 517–584, 548–563, 574–602

Glycosylation sites (5): 127, 308, 396, 453, 494

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1592389	Activation of Matrix Metalloproteinases
R-HSA-9657688	Defective factor XII causes hereditary angioedema
R-HSA-9657689	Defective SERPING1 causes hereditary angioedema
R-HSA-9855719	Regulation of FXIIa and plasma kallikrein activity
R-HSA-9935598	FXIIa, PKa-dependent activation of coagulation pathway
R-HSA-9970672	FXIIa activates plasma kallikrein-kinin system
R-HSA-140837
R-HSA-109582	Hemostasis
R-HSA-140877
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization
R-HSA-1643685	Disease
R-HSA-9651496
R-HSA-9671793	Diseases of hemostasis

MSigDB gene sets: 243 (showing top): GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_PROTEIN_ACTIVATION_CASCADE, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_COAGULATION, GOCC_SECRETORY_GRANULE, LI_PROSTATE_CANCER_EPIGENETIC, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, TGACCTY_ERR1_Q2, CHANDRAN_METASTASIS_DN, GOBP_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_COAGULATION

GO Biological Process (9): Factor XII activation (GO:0002542), proteolysis (GO:0006508), blood coagulation (GO:0007596), zymogen activation (GO:0031638), plasminogen activation (GO:0031639), fibrinolysis (GO:0042730), positive regulation of fibrinolysis (GO:0051919), inflammatory response (GO:0006954), hemostasis (GO:0007599)

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 (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Defects of contact activation system and kallikrein-kinin system	2
Degradation of the extracellular matrix	1
FXIIa activates plasma kallikrein-kinin system	1
Regulation of clotting cascade	1
Innate Immune System	1
Extracellular matrix organization	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of blood coagulation	2
plasma kallikrein-kinin cascade	1
activation of plasma proteins involved in acute inflammatory response	1
regulation of acute inflammatory response	1
positive regulation of protein processing	1
protein metabolic process	1
hemostasis	1
wound healing	1
coagulation	1
protein processing	1
zymogen activation	1
fibrinolysis	1
positive regulation of biological process	1
regulation of fibrinolysis	1
defense response	1
regulation of body fluid levels	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
cellular anatomical structure	1
membrane	1
cell periphery	1
extracellular vesicle	1

Protein interactions and networks

STRING

1476 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLKB1	KNG1	P01042	998
KLKB1	SERPING1	P05155	989
KLKB1	ACP3	P15309	934
KLKB1	SLC45A3	Q96JT2	859
KLKB1	A2M	P01023	847
KLKB1	SERPINA5	P05154	846
KLKB1	TGM4	P49221	826
KLKB1	F3	P13726	821
KLKB1	SERPINF2	P08697	804
KLKB1	MSMB	P08118	798
KLKB1	SERPINC1	P01008	743
KLKB1	GBA1	P04062	738
KLKB1	AR	P10275	732
KLKB1	REN	P00797	687
KLKB1	ANO7	Q6IWH7	686

IntAct

45 interactions, top by confidence:

A	B	Type	Score
KLKB1	NME4	psi-mi:“MI:0915”(physical association)	0.560
KLKB1	NPHP1	psi-mi:“MI:0915”(physical association)	0.560
PRRG2	KLKB1	psi-mi:“MI:0915”(physical association)	0.560
PSMD9	KLKB1	psi-mi:“MI:0915”(physical association)	0.560
EIF2B4	KLKB1	psi-mi:“MI:0915”(physical association)	0.560
KLKB1	PRMT5	psi-mi:“MI:0915”(physical association)	0.560
KLKB1	TGOLN2	psi-mi:“MI:0915”(physical association)	0.560
SNX12	KLKB1	psi-mi:“MI:0915”(physical association)	0.560
KLKB1	SLFN12	psi-mi:“MI:0915”(physical association)	0.560
KLKB1	TMEM185A	psi-mi:“MI:0915”(physical association)	0.560
CCDC26	KLKB1	psi-mi:“MI:0915”(physical association)	0.560
VKORC1L1	KLKB1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (16): GPHN (Affinity Capture-MS), ZBTB1 (Affinity Capture-MS), NCAPH (Affinity Capture-MS), CNOT2 (Affinity Capture-MS), KLKB1 (Affinity Capture-MS), KLKB1 (Reconstituted Complex), KNG1 (Reconstituted Complex), KLKB1 (Reconstituted Complex), KLKB1 (Reconstituted Complex), NID2 (Affinity Capture-MS), FBN2 (Affinity Capture-MS), ZBTB1 (Affinity Capture-MS), GPHN (Affinity Capture-MS), TOR3A (Affinity Capture-MS), NCAPH (Affinity Capture-MS)

ESM2 similar proteins: A6MFK7, A6MFK8, B5G6G5, P00741, P00750, P03951, P03952, P11214, P14210, P14272, P15638, P17945, P19637, P26262, P33587, P81428, P82807, P83370, P86091, P98119, P98121, Q05589, Q08048, Q1L658, Q28198, Q2KJ63, Q56VR3, Q58L93, Q58L94, Q58L95, Q58L96, Q5NTB3, Q5RDI1, Q5RF29, Q66TN7, Q6DIV5, Q6IE14, Q6SA95, Q6UXH9, Q6ZWK6

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

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
F12	“up-regulates activity”	KLKB1	cleavage
KLKB1	“up-regulates activity”	F12	cleavage
KLKB1	“up-regulates activity”	KNG1	cleavage
KLKB1	“up-regulates activity”	MST1	cleavage
KLKB1	“up-regulates activity”	HGF	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	128
Likely benign	23
Benign	50

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
12033	NM_000892.5(KLKB1):c.337C>T (p.Arg113Ter)	Pathogenic
12034	NM_000892.5(KLKB1):c.1205G>A (p.Trp402Ter)	Pathogenic
12036	NM_000892.5(KLKB1):c.367G>A (p.Gly123Arg)	Pathogenic
1803727	NM_000892.5(KLKB1):c.143_221+128del	Pathogenic
1803774	NM_000892.5(KLKB1):c.1196G>A (p.Trp399Ter)	Pathogenic
1801471	NM_000892.5(KLKB1):c.689T>A (p.Ile230Asn)	Likely pathogenic
2633368	NM_000892.5(KLKB1):c.1004del (p.Leu335fs)	Likely pathogenic
3065306	NM_000892.5(KLKB1):c.870del (p.Glu290fs)	Likely pathogenic
3068022	NM_000892.5(KLKB1):c.940G>T (p.Gly314Ter)	Likely pathogenic
3779797	NM_000892.5(KLKB1):c.1606C>T (p.Gln536Ter)	Likely pathogenic
4081475	NM_000892.5(KLKB1):c.204_207del (p.Ile68fs)	Likely pathogenic

SpliceAI

2622 predictions. Top by Δscore:

Variant	Effect	Δscore
4:186251208:A:AG	acceptor_gain	1.0000
4:186251633:GACT:G	donor_gain	1.0000
4:186251642:G:GT	donor_gain	1.0000
4:186251645:GAGAA:G	donor_gain	1.0000
4:186251647:G:GT	donor_gain	1.0000
4:186251647:GAA:G	donor_gain	1.0000
4:186251650:G:GG	donor_gain	1.0000
4:186251656:G:GT	donor_gain	1.0000
4:186251657:A:T	donor_gain	1.0000
4:186255989:CA:C	acceptor_loss	1.0000
4:186255990:A:AG	acceptor_gain	1.0000
4:186255991:G:GG	acceptor_gain	1.0000
4:186255991:GA:G	acceptor_gain	1.0000
4:186256083:GAAAG:G	donor_gain	1.0000
4:186256085:AAGG:A	donor_loss	1.0000
4:186256086:AGG:A	donor_loss	1.0000
4:186256088:GTAAG:G	donor_loss	1.0000
4:186227569:G:GT	donor_gain	0.9900
4:186227581:TTTTC:T	donor_gain	0.9900
4:186227584:TCAG:T	donor_loss	0.9900
4:186227585:CAGGT:C	donor_loss	0.9900
4:186227586:AGGT:A	donor_loss	0.9900
4:186227587:GG:G	donor_loss	0.9900
4:186227588:G:GA	donor_loss	0.9900
4:186227589:T:A	donor_loss	0.9900
4:186229902:G:GT	donor_gain	0.9900
4:186232126:GGAT:G	acceptor_gain	0.9900
4:186233930:A:G	acceptor_gain	0.9900
4:186236779:A:AG	acceptor_gain	0.9900
4:186236780:G:GG	acceptor_gain	0.9900

AlphaMissense

4205 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:186256068:G:C	W522C	0.997
4:186256068:G:T	W522C	0.997
4:186232249:A:C	S61R	0.996
4:186232251:T:A	S61R	0.996
4:186232251:T:G	S61R	0.996
4:186254727:G:C	A485P	0.995
4:186256066:T:A	W522R	0.995
4:186256066:T:C	W522R	0.995
4:186257327:T:A	C563S	0.995
4:186257328:G:C	C563S	0.995
4:186252127:T:A	C419S	0.994
4:186252128:G:C	C419S	0.994
4:186252177:C:G	C435W	0.994
4:186254728:C:A	A485D	0.994
4:186257282:T:A	C548S	0.994
4:186257283:G:C	C548S	0.994
4:186252091:A:C	S407R	0.993
4:186252093:C:A	S407R	0.993
4:186252093:C:G	S407R	0.993
4:186257327:T:C	C563R	0.993
4:186257360:T:A	C574S	0.993
4:186257361:G:C	C574S	0.993
4:186252082:T:A	W404R	0.992
4:186252082:T:C	W404R	0.992
4:186258084:A:C	S597R	0.992
4:186258086:C:A	S597R	0.992
4:186258086:C:G	S597R	0.992
4:186258089:G:C	W598C	0.992
4:186258089:G:T	W598C	0.992
4:186257329:T:G	C563W	0.991

dbSNP variants (sampled 300 via entrez): RS1000106803 (4:186236718 G>A), RS10001093 (4:186220788 C>G), RS1000125209 (4:186213457 G>T), RS1000222461 (4:186236416 A>G), RS1000364952 (4:186247503 C>T), RS1000367094 (4:186231775 G>GA), RS10004932 (4:186216328 G>A,T), RS1000497500 (4:186213254 T>C), RS1000571015 (4:186249304 T>C), RS1000616743 (4:186241128 G>A,C), RS1000636871 (4:186209340 C>A), RS1000676521 (4:186244247 T>G), RS1000748487 (4:186244432 G>A), RS1000859707 (4:186246492 C>G,T), RS1000860297 (4:186252754 C>T)

Disease associations

OMIM: gene MIM:229000 | disease phenotypes: MIM:612423, MIM:612089, MIM:210370

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited prekallikrein deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
inherited prekallikrein deficiency	Definitive	AR

Mondo (7): prekallikrein deficiency (MONDO:0044744), inherited prekallikrein deficiency (MONDO:0012901), hypophosphatemic rickets and hyperparathyroidism (MONDO:0012795), hereditary angioedema with normal C1Inh (MONDO:0100567), Bietti crystalline corneoretinal dystrophy (MONDO:0008865), corneal dystrophy (MONDO:0018102), thrombocytopenia (MONDO:0002049)

Orphanet (4): Congenital prekallikrein deficiency (Orphanet:749), Hereditary angioedema with normal C1Inh (Orphanet:528647), Corneal dystrophy (Orphanet:34533), Bietti crystalline dystrophy (Orphanet:41751)

HPO phenotypes

5 total (6 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001892	Abnormal bleeding
HP:0003584	Late onset
HP:0003645	Prolonged partial thromboplastin time
HP:0034371	Decreased circulating prekallikrein concentration
HP:0001131	Corneal dystrophy

GWAS associations

51 associations (top):

Study	Trait	p-value
GCST000152_3	Prostate cancer	2.000000e-18
GCST000635_25	Response to statin therapy	3.000000e-06
GCST000919_3	Serum prostate-specific antigen levels	3.000000e-46
GCST001217_32	Metabolic traits	7.000000e-18
GCST001391_10	Metabolite levels	6.000000e-13
GCST001639_20	Metabolite levels	4.000000e-12
GCST001762_822	Obesity-related traits	9.000000e-08
GCST001796_3	Prostate-specific antigen levels	6.000000e-37
GCST001853_2	Circulating vasoactive peptide levels	4.000000e-52
GCST001853_3	Circulating vasoactive peptide levels	1.000000e-122
GCST001946_4	PCA3 expression level	1.000000e-08
GCST002112_14	Celiac disease	6.000000e-06
GCST002388_15	Serum metabolite levels	7.000000e-25
GCST002388_2	Serum metabolite levels	9.000000e-27
GCST002413_1	Prostate cancer (early onset)	1.000000e-07
GCST002421_4	Prostate cancer	2.000000e-28
GCST002476_2	Prostate-specific antigen levels	8.000000e-21
GCST002703_4	Prostate-specific antigen levels	9.000000e-21
GCST002714_3	Plasma renin activity levels	6.000000e-08
GCST002736_2	B-type natriuretic peptide levels	2.000000e-11
GCST002886_3	Prostate cancer aggressiveness	6.000000e-09
GCST002944_1	Prostate cancer	1.000000e-13
GCST003590_2	Apolipoprotein A-IV levels	6.000000e-14
GCST003793_1	L-arginine levels	2.000000e-22
GCST004038_1	Circulating chromogranin peptide levels	3.000000e-30
GCST004038_2	Circulating chromogranin peptide levels	1.000000e-07
GCST004093_17	Prostate-specific antigen levels	9.000000e-186
GCST004093_18	Prostate-specific antigen levels	2.000000e-111
GCST004093_19	Prostate-specific antigen levels	8.000000e-17
GCST004093_2	Prostate-specific antigen levels	0.000000e+00

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0004723	coronary artery calcification
EFO:0004627	IGF-1 measurement
EFO:0005196	vasoactive peptide measurement
EFO:0005127	cancer biomarker measurement
EFO:0006828	plasma renin activity measurement
EFO:0006920	BNP measurement
EFO:0006999	cancer aggressiveness measurement
EFO:0007000	Gleason score measurement
EFO:0007848	apolipoprotein A-IV measurement
EFO:0006524	L-arginine measurement
EFO:0007909	CHGA cleavage product measurement
EFO:0007910	CHGB cleavage product measurement
EFO:0009767	glycine measurement
EFO:0010071	cardiac troponin I measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003317	Corneal Dystrophies, Hereditary	C11.204.236; C11.270.162; C16.320.290.162
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C535440	Bietti Crystalline Dystrophy (supp.)
C567423	Hypophosphatemic Rickets And Hyperparathyroidism (supp.)
C562725	Prekallikrein Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2000 (SINGLE PROTEIN), CHEMBL2111419 (SELECTIVITY GROUP)

Molecules with ChEMBL bioactivity

10 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,565 (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
CHEMBL5189739	BEROTRALSTAT	4	7
CHEMBL1922235	DAREXABAN	3	710
CHEMBL4112929	MILVEXIAN	3	134
CHEMBL4297502	AVORALSTAT	3	91
CHEMBL5095248	SEBETRALSTAT	3	102
CHEMBL87563	GABEXATE	3	2,031
CHEMBL1095032	LETAXABAN	2	375
CHEMBL220050	GW813893	2	73
CHEMBL5095064	FENIRALSTAT	2	13
CHEMBL4073292	BMS-962212	1	29

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
lanadelumab	Binding	10.05	pIC50
berotralstat	Inhibition	10.0	pKi
compound 11 [PMID: 16413183]	Inhibition	9.3	pKi
avoralstat	Inhibition	8.7	pIC50
sebetralstat	Inhibition	8.22	pIC50
milvexian	Inhibition	7.36	pKi

Binding affinities (BindingDB)

2156 measured of 3057 human assays (3083 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-[(2-oxo-1-pyridinyl)methyl]phenyl]methyl]pyrazole-4-carboxamide	IC50	0.0224 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-[(3,5-dimethylpyrazol-1-yl)methyl]phenyl]methyl]triazole-4-carboxamide	IC50	0.03 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.03 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]pyrazole-4-carboxamide	IC50	0.04 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
methyl N-[(10R,14S)-14-[4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,18-diazatricyclo[13.3.1.02,7]nonadeca-1(18),2(7),3,5,15(19),16-hexaen-5-yl]carbamate	KI	0.04 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one	KI	0.05 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-17-chloro-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16,18-triazatricyclo[13.2.1.02,7]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate	KI	0.05 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.06 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(13R,17S)-17-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-6,13-dimethyl-12-oxo-7,11,19-triazatetracyclo[16.3.1.02,10.04,8]docosa-1(22),2(10),3,5,8,18,20-heptaene-5-carboxylic acid	KI	0.06 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-4,5-difluoro-10-methyl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one	KI	0.07 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
2-[(2-methylpropan-2-yl)oxy]ethyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.08 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
2-hydroxyethyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.08 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-17-methoxy-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.09 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-[5-chloro-2-(trifluoromethyl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.09 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(10S,14S)-14-[4-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-propan-2-yl-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2,4,6,15,17-hexaen-9-one	KI	0.09 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[3-methoxy-4-(pyrazol-1-ylmethyl)phenyl]methyl]pyrazole-4-carboxamide	IC50	0.0912 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-[(5-methylpyrazol-1-yl)methyl]phenyl]methyl]triazole-4-carboxamide	IC50	0.1 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[(1,2-dimethylindol-5-yl)methyl]pyrazole-4-carboxamide	IC50	0.1 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
methyl N-[(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.1 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-ethynyl-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.1 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
(9R,13S)-13-[4-[5-chloro-2-(4-chlorotriazol-1-yl)phenyl]-6-oxo-1,3-diazinan-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetrazatricyclo[12.3.1.02,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one	KI	0.1 nM	US-9453018: Pyrimidinones as factor XIa inhibitors
(9R,13S)-13-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-6-oxo-1,3-diazinan-1-yl]-3,9-dimethyl-3,4,7,15-tetrazatricyclo[12.3.1.02,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one	KI	0.1 nM	US-9453018: Pyrimidinones as factor XIa inhibitors
(9R,13S)-13-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-6-oxo-1,3-diazinan-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetrazatricyclo[12.3.1.02,6]octadeca-1(18),2(6),4,14,16-pentaen-8-one	KI	0.1 nM	US-9453018: Pyrimidinones as factor XIa inhibitors
(9R,13S)-13-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-6-oxo-1,3-diazinan-1-yl]-3,9-dimethyl-3,4,7,17-tetrazatricyclo[12.3.1.02,6]octadeca-1(17),2(6),4,14(18),15-pentaen-8-one	KI	0.1 nM	US-9453018: Pyrimidinones as factor XIa inhibitors
BDBM304229	IC50	0.1 nM	US-10143681: Factor XIa inhibitors
7-[[6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-3-pyridinyl]methyl]-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrrolo[2,3-d]pyrimidine-5-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-3-pyridinyl]methyl]-3-(difluoromethyl)-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrazole-4-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
1-[[6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-3-pyridinyl]methyl]-3-(methoxymethyl)-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrazole-4-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-3-pyridinyl]methyl]-3-(methoxymethyl)-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrazole-4-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
7-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-3-pyridinyl]methyl]-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrrolo[2,3-d]pyrimidine-5-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
1-[[6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-3-pyridinyl]methyl]-3-methyl-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrazole-4-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
7-[[2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-methylpyrimidin-5-yl]methyl]-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrrolo[2,3-d]pyrimidine-5-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
1-[[6-(5-azaspiro[2.3]hexan-5-yl)-2-methyl-3-pyridinyl]methyl]-3-(methoxymethyl)-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrazole-4-carboxamide	KI	0.1 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
methyl N-[(10R,14S)-14-[4-[3-chloro-2-fluoro-6-(2H-triazol-4-yl)phenyl]-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.11 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-[(3,5-dimethylpyrazol-1-yl)methyl]phenyl]methyl]pyrazole-4-carboxamide	IC50	0.134 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
(R)-trans-4-{[2-{5-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-1-oxidopyridin-2-yl}-3-(4-hydroxycyclohexyl)propanoyl]amino}benzoic Acid	IC50	0.14 nM	US-10143681: Factor XIa inhibitors
methyl N-[(10R,14S)-14-[4-(6-acetyl-3-chloro-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8-azatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.17 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
methyl N-[(10S,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-11-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.18 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
methyl N-[(10S,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-11-fluoro-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	KI	0.18 nM	US-9951071: Dihydropyridone P1 as factor XIa inhibitors
4-[[(2R)-2-[5-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-1-oxidopyridin-1-ium-2-yl]-3-(2-methylcyclopropyl)propanoyl]amino]benzoic acid	IC50	0.19 nM	US-10143681: Factor XIa inhibitors
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]imidazole-4-carboxamide	IC50	0.2 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]pyrazole-4-carboxamide	IC50	0.2 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[(1,2,3-trimethylindol-5-yl)methyl]triazole-4-carboxamide	IC50	0.2 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
N-[(6-amino-4-chloro-2-methyl-3-pyridinyl)methyl]-1-[[4-[(2-oxo-1-pyridinyl)methyl]phenyl]methyl]pyrazole-4-carboxamide	IC50	0.2 nM	US-9290485: N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
methyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10,17-dimethyl-9-oxo-8,16,18-triazatricyclo[13.2.1.02,7]octadeca-1(17),2(7),3,5,15(18)-pentaen-5-yl]carbamate	KI	0.2 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors
(9R,13S)-13-[4-[5-chloro-2-(4-chlorotriazol-1-yl)phenyl]-6-oxo-1,3-diazinan-1-yl]-3,9-dimethyl-3,4,7,17-tetrazatricyclo[12.3.1.02,6]octadeca-1(17),2(6),4,14(18),15-pentaen-8-one	KI	0.2 nM	US-9453018: Pyrimidinones as factor XIa inhibitors
1-[4-chloro-2-[1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetrazatricyclo[12.3.1.02,6]octadeca-1(17),2(6),4,14(18),15-pentaen-13-yl]-6-oxo-1,3-diazinan-4-yl]phenyl]triazole-4-carboxylic acid	KI	0.2 nM	US-9453018: Pyrimidinones as factor XIa inhibitors
1-[4-chloro-2-[1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetrazatricyclo[12.3.1.02,6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,3-diazinan-4-yl]phenyl]triazole-4-carboxylic acid	KI	0.2 nM	US-9453018: Pyrimidinones as factor XIa inhibitors
1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-3-pyridinyl]methyl]-3-methoxy-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]pyrazole-4-carboxamide	KI	0.2 nM	US-10695334: Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors
methyl N-[(10R,14S)-14-[4-(3-chloro-6-cyano-2-fluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9,17-dioxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-2(7),3,5-trien-5-yl]carbamate	KI	0.21 nM	US-9409908: Dihydropyridone p1 as factor XIa inhibitors

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.72	Ki	0.019	nM	CHEMBL4471466
10.70	Ki	0.02	nM	CHEMBL4238882
10.65	IC50	0.0224	nM	CHEMBL3969639
10.52	IC50	0.03	nM	CHEMBL3897372
10.40	IC50	0.04	nM	CHEMBL3982813
10.22	Ki	0.06	nM	CHEMBL4089486
10.15	Ki	0.07	nM	CHEMBL4079711
10.12	Ki	0.075	nM	CHEMBL2016865
10.04	IC50	0.0912	nM	CHEMBL3901955
10.00	IC50	0.1	nM	CHEMBL3912934
10.00	IC50	0.1	nM	CHEMBL3953631
10.00	Ki	0.1	nM	CHEMBL4524734
10.00	IC50	0.1	nM	CHEMBL5082614
10.00	Ki	0.1	nM	CHEMBL4852994
10.00	Ki	0.1	nM	CHEMBL5283976
10.00	Ki	0.1	nM	CHEMBL5938427
10.00	Ki	0.1	nM	CHEMBL6050133
10.00	Ki	0.1	nM	CHEMBL5872101
10.00	Ki	0.1	nM	CHEMBL5955377
10.00	Ki	0.1	nM	CHEMBL5883536
10.00	Ki	0.1	nM	CHEMBL6007797
10.00	Ki	0.1	nM	CHEMBL5866744
10.00	Ki	0.1	nM	CHEMBL6021310
10.00	Ki	0.1	nM	CHEMBL5935005
9.87	IC50	0.134	nM	CHEMBL3893209
9.85	Ki	0.14	nM	CHEMBL4099333
9.82	Ki	0.15	nM	CHEMBL4093698
9.80	Ki	0.16	nM	CHEMBL5960612
9.77	Ki	0.17	nM	CHEMBL5800384
9.70	IC50	0.2	nM	CHEMBL3934425
9.70	IC50	0.2	nM	CHEMBL3907471
9.70	IC50	0.2	nM	CHEMBL3958883
9.70	IC50	0.2	nM	CHEMBL3893365
9.70	IC50	0.2	nM	CHEMBL5079850
9.70	IC50	0.2	nM	CHEMBL5089406
9.70	IC50	0.2	nM	CHEMBL5078294
9.70	IC50	0.2	nM	CHEMBL5201574
9.70	Ki	0.2	nM	CHEMBL6004984
9.70	IC50	0.2	nM	CHEMBL6083089
9.68	Ki	0.21	nM	CHEMBL4076199
9.64	Ki	0.23	nM	CHEMBL5999519
9.60	Ki	0.25	nM	CHEMBL4070056
9.59	Ki	0.26	nM	AVORALSTAT
9.59	Ki	0.26	nM	CHEMBL5865959
9.55	Ki	0.28	nM	CHEMBL6017899
9.52	Ki	0.3	nM	CHEMBL2448529
9.52	Ki	0.3	nM	CHEMBL3660174
9.52	IC50	0.3	nM	CHEMBL4853430
9.52	IC50	0.3	nM	CHEMBL4875151
9.52	IC50	0.3	nM	CHEMBL5079924

PubChem BioAssay actives

715 with measured affinity, of 1311 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
3-[[(2R)-1-[[(2S)-1-[3-(aminomethyl)phenyl]-4-(4-carbamimidoylphenyl)-3-oxobutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	1393342: Competitive inhibition of human plasma kallikrein using S2302 as substrate by UV-visible spectrophotometer	ki	<0.0001	uM
3-[[(2R)-1-[[(2S)-3-[3-(aminomethyl)phenyl]-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	1558641: Inhibition of human plasma kallikrein by Michaelis-menten analysis	ki	<0.0001	uM
1-[3-(aminomethyl)phenyl]-5-N-[5-[(cyclopropylmethylamino)-phenylmethyl]-2-fluorophenyl]pyrazole-3,5-dicarboxamide	1930747: Inhibition of human plasma kallikrein using H-D-Pro-Phe-Arg-p-nitroaniline as substrate assessed as inhibition constant	ki	0.0001	uM
(7R,10S,13S,21S,24S,27R,30S,33S,36S,39S,42S,45R)-7-acetamido-36-(3-amino-3-oxopropyl)-24-(3-carbamimidamidopropyl)-39-(carboxymethyl)-10-(hydroxymethyl)-33-(1H-imidazol-5-ylmethyl)-13-(1H-indol-3-ylmethyl)-21-methyl-30,42-bis(2-methylpropyl)-8,11,14,19,22,25,28,31,34,37,40,43-dodecaoxo-5,47,52-trithia-9,12,15,20,23,26,29,32,35,38,41,44-dodecazatetracyclo[25.23.3.13,49.015,18]tetrapentaconta-1,3(54),49-triene-45-carboxylic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0001	uM
(2S)-2-[[(7R,10S,13S,19S,22S,25S,28R,31S,34S,37S,40S,43S,46R)-37-(3-amino-3-oxopropyl)-7-[[(2S)-2-aminopropanoyl]amino]-25-(3-carbamimidamidopropyl)-40-(carboxymethyl)-10-(hydroxymethyl)-34-(1H-imidazol-5-ylmethyl)-13-(1H-indol-3-ylmethyl)-22-methyl-31,43-bis(2-methylpropyl)-8,11,14,20,23,26,29,32,35,38,41,44-dodecaoxo-5,48,53-trithia-9,12,15,21,24,27,30,33,36,39,42,45-dodecazatetracyclo[26.23.3.13,50.015,19]pentapentaconta-1,3(55),50-triene-46-carbonyl]amino]propanoic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0001	uM
(7R,10S,13S,19S,22S,25S,28R,31S,34S,37S,40S,43S,46R)-7-acetamido-37-(3-amino-3-oxopropyl)-25-(3-carbamimidamidopropyl)-40-(carboxymethyl)-10-(hydroxymethyl)-34-(1H-imidazol-5-ylmethyl)-13-(1H-indol-3-ylmethyl)-22-methyl-31,43-bis(2-methylpropyl)-8,11,14,20,23,26,29,32,35,38,41,44-dodecaoxo-5,48,53-trithia-9,12,15,21,24,27,30,33,36,39,42,45-dodecazatetracyclo[26.23.3.13,50.015,19]pentapentaconta-1,3(55),50-triene-46-carboxylic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0001	uM
(7R,10S,13S,21S,24S,27R,30S,33S,36S,39S,42S,45R)-7-acetamido-36-(3-amino-3-oxopropyl)-24-(4-carbamimidamidobutyl)-39-(carboxymethyl)-10-(hydroxymethyl)-33-(1H-imidazol-5-ylmethyl)-13-(1H-indol-3-ylmethyl)-21-methyl-30,42-bis(2-methylpropyl)-8,11,14,19,22,25,28,31,34,37,40,43-dodecaoxo-5,47,52-trithia-9,12,15,20,23,26,29,32,35,38,41,44-dodecazatetracyclo[25.23.3.13,49.015,18]tetrapentaconta-1,3(54),49-triene-45-carboxylic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0001	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-3-(hydroxymethyl)-N-[1-[1-[6-methyl-5-[(1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl]pyrazin-2-yl]ethyl]pyrazol-4-yl]pyrazine-2-carboxamide	1816014: Inhibition of human plasma kallikrein using fluorogenic substrate measured by microplate reader analysis	ic50	0.0001	uM
(2S)-3-[3-(aminomethyl)phenyl]-2-[[(2R)-2-(benzylsulfonylamino)-3-naphthalen-2-ylpropanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]propanamide	1558646: Inhibition of human plasma kallikrein using S2302 as substrate after 10 mins by UV/Vis photometry	ki	0.0001	uM
3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-[3-[(diaminomethylideneamino)methyl]phenyl]-1-oxopropan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	656101: Inhibition of plasma kallikrein by dixon plot method	ki	0.0001	uM
1-[3-(aminomethyl)phenyl]-N-[3-[cyclopropylmethoxy(phenyl)methyl]phenyl]-3-(trifluoromethyl)pyrazole-5-carboxamide	1930747: Inhibition of human plasma kallikrein using H-D-Pro-Phe-Arg-p-nitroaniline as substrate assessed as inhibition constant	ki	0.0001	uM
(7R,10S,13S,21S,24S,27R,30S,33S,36S,39S,42S,45R)-7-acetamido-36-(3-amino-3-oxopropyl)-13-benzyl-24-(4-carbamimidamidobutyl)-39-(carboxymethyl)-10-(hydroxymethyl)-21-[(4-hydroxyphenyl)methyl]-33-(1H-imidazol-5-ylmethyl)-30,42-bis(2-methylpropyl)-8,11,14,19,22,25,28,31,34,37,40,43-dodecaoxo-5,47,52-trithia-9,12,15,20,23,26,29,32,35,38,41,44-dodecazatetracyclo[25.23.3.13,49.015,18]tetrapentaconta-1,3(54),49-triene-45-carboxylic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0002	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-3-methyl-N-[1-[[5-methyl-6-[(1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl]-3-pyridinyl]methyl]pyrazol-4-yl]pyrazine-2-carboxamide	1816014: Inhibition of human plasma kallikrein using fluorogenic substrate measured by microplate reader analysis	ic50	0.0002	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-3-(hydroxymethyl)-N-[1-[1-[5-methyl-6-[(1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl]-3-pyridinyl]ethyl]pyrazol-4-yl]pyrazine-2-carboxamide	1816014: Inhibition of human plasma kallikrein using fluorogenic substrate measured by microplate reader analysis	ic50	0.0002	uM
6-(3-chloro-6-cyano-2-fluorophenyl)-N-[1-[1-[5-fluoro-4-methyl-6-[(1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl]-3-pyridinyl]ethyl]pyrazol-4-yl]-3-methylpyrazine-2-carboxamide	1816014: Inhibition of human plasma kallikrein using fluorogenic substrate measured by microplate reader analysis	ic50	0.0002	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[[2-[2-[[(1-hydroxycyclopropyl)methyl-methylamino]methyl]pyrrolidin-1-yl]pyrimidin-5-yl]methyl]pyrazol-4-yl]pyrazine-2-carboxamide	1880782: Inhibition of human plasma kallikrein assessed as substrate hydrolysis using acetyl-K-P-R-AFC as substrate by spectrofluorometric analysis	ic50	0.0002	uM
N-[(6-amino-2,4-dimethyl-3-pyridinyl)methyl]-1-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]imidazole-4-carboxamide	1930743: Inhibition of human plasma kallikrein incubated for 1 hrs	ic50	0.0002	uM
(2R)-2-[[(2R)-2-[[2-[[2-[[2-[[(2S)-2-[[(7R,10S,13S,16S,22S,25S,28S,31R,34S,37S,45S,48S,51R)-51-acetamido-45-benzyl-10-[(2S)-butan-2-yl]-34-(4-carbamimidamidobutyl)-13-(carboxymethyl)-48-(hydroxymethyl)-22,25,37-tris[(4-hydroxyphenyl)methyl]-9,12,15,21,24,27,30,33,36,39,44,47,50-tridecaoxo-28-propan-2-yl-5,53,58-trithia-8,11,14,20,23,26,29,32,35,38,43,46,49-tridecazapentacyclo[29.25.3.13,55.016,20.040,43]hexaconta-1(56),2,55(60)-triene-7-carbonyl]amino]propanoyl]-methylamino]acetyl]-methylamino]acetyl]-methylamino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0003	uM
1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-5-cyano-4-methyl-3-pyridinyl]methyl]-N-[(6R)-3-methyl-5,6-dihydro-4H-cyclopenta[d]imidazol-6-yl]imidazole-4-carboxamide	1772181: Inhibition of human plasma kallikrein using H-Pro-Phe-AMC as fluorogenic substrate measured every 2 mins for 12 mins by microplate reader analysis	ic50	0.0003	uM
1-[[4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-cyano-2-methylphenyl]methyl]-N-[(6R)-3-methyl-5,6-dihydro-4H-cyclopenta[d]imidazol-6-yl]imidazole-4-carboxamide	1772181: Inhibition of human plasma kallikrein using H-Pro-Phe-AMC as fluorogenic substrate measured every 2 mins for 12 mins by microplate reader analysis	ic50	0.0003	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[(1S)-1-[5-fluoro-4-methyl-6-[(1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl]-3-pyridinyl]ethyl]pyrazol-4-yl]pyrazine-2-carboxamide	1816014: Inhibition of human plasma kallikrein using fluorogenic substrate measured by microplate reader analysis	ic50	0.0003	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[1-[5-methoxy-4-methyl-6-[(1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl]-3-pyridinyl]ethyl]pyrazol-4-yl]pyrazine-2-carboxamide	1816014: Inhibition of human plasma kallikrein using fluorogenic substrate measured by microplate reader analysis	ic50	0.0003	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[[2-[(1R,2S,5S)-2-[[(2-hydroxy-2-methylpropyl)amino]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]pyrimidin-5-yl]methyl]pyrazol-4-yl]pyrazine-2-carboxamide	1880782: Inhibition of human plasma kallikrein assessed as substrate hydrolysis using acetyl-K-P-R-AFC as substrate by spectrofluorometric analysis	ic50	0.0003	uM
N-[(2-fluoro-4-methylphenyl)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]pyrazole-4-carboxamide	1985691: Inhibition of human PKa using H-D-Pro-Phe-Arg-AFC peptide substrate measured after 60 mins by fluorometric assay	ic50	0.0003	uM
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(cyclopropanecarbonyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	1558653: Inhibition of human plasma kallikrein using S2302 as substrate	ki	0.0003	uM
2-[[(1R,7S,13S,16S,19S,22R,34R,43S,49S)-34-[(2-aminoacetyl)amino]-43-[3-(diaminomethylideneamino)propyl]-19-[(4-hydroxyphenyl)methyl]-16-methyl-2,8,14,17,20,35,38,41,44,50-decaoxo-24,32,53-trithia-3,9,15,18,21,36,39,42,45,51-decazahexacyclo[26.23.3.126,30.03,7.09,13.045,49]pentapentaconta-26,28,30(55)-triene-22-carbonyl]amino]acetic acid	736244: Inhibition of human recombinant polyhistidine-tagged plasma kallikrein expressed in Escherichia coli XL1 blue using Z-FR-AMC as substrate by fluorimetric analysis	ki	0.0003	uM
3-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-ethenyl-5-methoxyphenyl]-6-(cyclopropylmethylcarbamoyl)pyridine-2-carboxylic acid	1784731: Inhibition of purified human plasma kallikrein assessed as inhibition constant using H-D-Pro-Phe-Arg-pNA.2HCl as substrate measured after 3 mins by microplate reader analysis	ki	0.0003	uM
(2S)-2-[[(7R,10S,13S,16S,22S,25S,28S,31R,34S,37S,40S,46S,49S,52S,55R)-49,52-bis(2-amino-2-oxoethyl)-55-[[(2S)-2-aminopropanoyl]amino]-37,46-dibenzyl-10-[(2S)-butan-2-yl]-34-(3-carbamimidamidopropyl)-13-(carboxymethyl)-22,25-bis[(4-hydroxyphenyl)methyl]-9,12,15,21,24,27,30,33,36,39,45,48,51,54-tetradecaoxo-28-propan-2-yl-5,57,62-trithia-8,11,14,20,23,26,29,32,35,38,44,47,50,53-tetradecazapentacyclo[29.29.3.13,59.016,20.040,44]tetrahexaconta-1(60),2,59(64)-triene-7-carbonyl]amino]propanoic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0004	uM
(7R,10S,13S,19S,22S,25S,28R,31S,34S,37S,40S,43S,46R)-7-acetamido-37-(3-amino-3-oxopropyl)-13-benzyl-25-(3-carbamimidamidopropyl)-40-(carboxymethyl)-10-(hydroxymethyl)-22-[(4-hydroxyphenyl)methyl]-34-(1H-imidazol-5-ylmethyl)-31,43-bis(2-methylpropyl)-8,11,14,20,23,26,29,32,35,38,41,44-dodecaoxo-5,48,53-trithia-9,12,15,21,24,27,30,33,36,39,42,45-dodecazatetracyclo[26.23.3.13,50.015,19]pentapentaconta-1,3(55),50-triene-46-carboxylic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0004	uM
(7R,10S,13S,21S,24S,27S,30S,33S,36S,39S,42S,45R)-7-acetamido-36-(3-amino-3-oxopropyl)-13-benzyl-24-(4-carbamimidamidobutyl)-39-(carboxymethyl)-10-(hydroxymethyl)-21-[(4-hydroxyphenyl)methyl]-33-(1H-imidazol-5-ylmethyl)-30-methyl-42-(2-methylpropyl)-8,11,14,19,22,25,28,34,37,40,43-undecaoxo-5,47,52-trithia-9,12,15,20,23,26,29,32,35,38,41,44-dodecazatetracyclo[25.23.3.13,49.015,18]tetrapentaconta-1,3(54),49-triene-45-carboxylic acid	1455787: Inhibition of human plasma kallikrein using fluorogenic H-Pro-Phe-Arg-AMC peptide as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence-based assay	ki	0.0004	uM
1-[[4-(3-azabicyclo[3.1.0]hexan-3-yl)-2-cyanophenyl]methyl]-N-[(6R)-3-methyl-5,6-dihydro-4H-cyclopenta[d]imidazol-6-yl]imidazole-4-carboxamide	1772181: Inhibition of human plasma kallikrein using H-Pro-Phe-AMC as fluorogenic substrate measured every 2 mins for 12 mins by microplate reader analysis	ic50	0.0004	uM
1-[[6-(3-azabicyclo[3.1.0]hexan-3-yl)-5-cyano-4-methyl-3-pyridinyl]methyl]-N-[(6R)-3-methyl-5,6-dihydro-4H-cyclopenta[d]imidazol-6-yl]pyrazole-4-carboxamide	1772181: Inhibition of human plasma kallikrein using H-Pro-Phe-AMC as fluorogenic substrate measured every 2 mins for 12 mins by microplate reader analysis	ic50	0.0004	uM
1-[[4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-cyano-2-methylphenyl]methyl]-N-[(6R)-3-methyl-5,6-dihydro-4H-cyclopenta[d]imidazol-6-yl]pyrazole-4-carboxamide	1772181: Inhibition of human plasma kallikrein using H-Pro-Phe-AMC as fluorogenic substrate measured every 2 mins for 12 mins by microplate reader analysis	ic50	0.0004	uM
1-[[2-cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)phenyl]methyl]-N-[(6R)-3-methyl-5,6-dihydro-4H-cyclopenta[d]imidazol-6-yl]imidazole-4-carboxamide	1772181: Inhibition of human plasma kallikrein using H-Pro-Phe-AMC as fluorogenic substrate measured every 2 mins for 12 mins by microplate reader analysis	ic50	0.0004	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[[2-[(2S)-2-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]pyrrolidin-1-yl]pyrimidin-5-yl]methyl]pyrazol-4-yl]pyrazine-2-carboxamide	1880782: Inhibition of human plasma kallikrein assessed as substrate hydrolysis using acetyl-K-P-R-AFC as substrate by spectrofluorometric analysis	ic50	0.0004	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[[2-[(1R,2S,5S)-2-[[[(2R)-1-hydroxypropan-2-yl]amino]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]pyrimidin-5-yl]methyl]pyrazol-4-yl]pyrazine-2-carboxamide	1880782: Inhibition of human plasma kallikrein assessed as substrate hydrolysis using acetyl-K-P-R-AFC as substrate by spectrofluorometric analysis	ic50	0.0004	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[[2-[(2S)-2-[(3-hydroxy-3-methylpyrrolidin-1-yl)methyl]pyrrolidin-1-yl]pyrimidin-5-yl]methyl]pyrazol-4-yl]pyrazine-2-carboxamide	1880782: Inhibition of human plasma kallikrein assessed as substrate hydrolysis using acetyl-K-P-R-AFC as substrate by spectrofluorometric analysis	ic50	0.0004	uM
2-[3-(6-carbamimidoyl-1H-benzimidazol-2-yl)-5-(3-carbamoylphenyl)-4-hydroxyphenyl]butanedioic acid	263035: Binding affinity to plasma kallikrein	ki	0.0005	uM
1-[[6-(5-azaspiro[2.3]hexan-5-yl)-2-(difluoromethyl)-3-pyridinyl]methyl]-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]triazole-4-carboxamide	1774650: Inhibition of kallikrein (unknown origin) using H-Pro-Phe-Arg-AMC as substrate incubated for 1 hr by fluorescence based analysis	ic50	0.0005	uM
1-[[6-(5-azaspiro[2.3]hexan-5-yl)-2-(difluoromethyl)-3-pyridinyl]methyl]-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]imidazole-4-carboxamide	1774650: Inhibition of kallikrein (unknown origin) using H-Pro-Phe-Arg-AMC as substrate incubated for 1 hr by fluorescence based analysis	ic50	0.0005	uM
(4R)-1’-[5-amino-1-[(4-methylphenyl)methyl]pyrazole-4-carbonyl]-6-chloro-5-fluorospiro[1H-3,1-benzoxazine-4,3’-piperidine]-2-one	1886981: Inhibition of purified human plasma kallikrein using Acetyl-K- P-R-AFC as substrate by fluorescence based spectrofluorimetric analysis	ic50	0.0005	uM
(4R)-1’-[5-amino-1-[(3-chlorophenyl)methyl]pyrazole-4-carbonyl]-6-chloro-5-fluorospiro[1H-3,1-benzoxazine-4,3’-piperidine]-2-one	1886981: Inhibition of purified human plasma kallikrein using Acetyl-K- P-R-AFC as substrate by fluorescence based spectrofluorimetric analysis	ic50	0.0005	uM
6-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-N-[1-[[2-[(1R,2S,5S)-2-[(3-hydroxy-3-methylazetidin-1-yl)methyl]-3-azabicyclo[3.1.0]hexan-3-yl]pyrimidin-5-yl]methyl]pyrazol-4-yl]pyrazine-2-carboxamide	1880782: Inhibition of human plasma kallikrein assessed as substrate hydrolysis using acetyl-K-P-R-AFC as substrate by spectrofluorometric analysis	ic50	0.0005	uM
6-[(4S)-6-chloro-5-fluoro-2-oxospiro[1H-3,1-benzoxazine-4,3’-pyrrolidine]-1’-yl]-N-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]pyridazine-4-carboxamide	1923223: Inhibition of human plasma kallikrein using Acetyl-K- P-R-AFC as substrate by fluorescence based analysis	ic50	0.0005	uM
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]pyrazole-4-carboxamide	1930744: Inhibition of human plasma kallikrein using H-DPro-Phe-Arg-AFC as substrate	ic50	0.0006	uM
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-pyridin-4-ylbutan-2-yl]-5-phenylpentanamide	1558646: Inhibition of human plasma kallikrein using S2302 as substrate after 10 mins by UV/Vis photometry	ki	0.0006	uM
1-[[6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-2-(difluoromethyl)-3-pyridinyl]methyl]-N-[(6R)-3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-6-yl]imidazole-4-carboxamide	1774650: Inhibition of kallikrein (unknown origin) using H-Pro-Phe-Arg-AMC as substrate incubated for 1 hr by fluorescence based analysis	ic50	0.0006	uM
(4R)-1’-[5-amino-1-[2,2,2-trifluoro-1-(1-fluorocyclopropyl)ethyl]pyrazole-4-carbonyl]-6-chloro-5-fluorospiro[1H-3,1-benzoxazine-4,3’-piperidine]-2-one	1886981: Inhibition of purified human plasma kallikrein using Acetyl-K- P-R-AFC as substrate by fluorescence based spectrofluorimetric analysis	ic50	0.0006	uM
(4R)-1’-[5-amino-1-[1-(oxan-4-yl)propyl]pyrazole-4-carbonyl]-6-chloro-5-fluorospiro[1H-3,1-benzoxazine-4,3’-piperidine]-2-one	1886981: Inhibition of purified human plasma kallikrein using Acetyl-K- P-R-AFC as substrate by fluorescence based spectrofluorimetric analysis	ic50	0.0006	uM
5-[(4S)-6-chloro-5-fluoro-2-oxospiro[1H-3,1-benzoxazine-4,3’-pyrrolidine]-1’-yl]-N-[[6-[(2-oxo-1-pyridinyl)methyl]-3-pyridinyl]methyl]pyridine-3-carboxamide	1923223: Inhibition of human plasma kallikrein using Acetyl-K- P-R-AFC as substrate by fluorescence based analysis	ic50	0.0006	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	8
Cyclosporine	decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression	3
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
GSK-J4	decreases expression	1
methyleugenol	decreases expression	1
gingerol	decreases reaction, increases expression, decreases expression	1
kojic acid	decreases expression	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	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
Rosiglitazone	decreases expression	1
Arsenic Trioxide	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	affects binding	1
Chlorpromazine	affects cotreatment, affects expression	1
Cholic Acids	affects expression, affects cotreatment	1
Chondroitin Sulfates	increases activity	1
Drugs, Chinese Herbal	increases expression	1
Estradiol	decreases expression	1
Lead	decreases expression	1
Methotrexate	increases expression	1

ChEMBL screening assays

300 unique, capped per target: 283 binding, 17 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005946	Binding	Inhibition of human kallikrein	Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors. — J Med Chem
CHEMBL4388472	ADMET	Inhibition of recombinant C-terminal 6-His tagged human KLKB1 (Gly20 to Ala638 residues) expressed in mouse NS0 cells using P-F-R-AMC as substrate after 40 mins by fluorescence intensity assay	Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT06743646	PHASE3	RECRUITING	Efficacy and Safety of ZVS101e in Patients With Bietti ’s Crystalline Dystrophy
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count