PROC

Summary

PROC (protein C, inactivator of coagulation factors Va and VIIIa, HGNC:9451) is a protein-coding gene on chromosome 2q14.3, encoding Vitamin K-dependent protein C (P04070). Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.

This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.

Source: NCBI Gene 5624 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary thrombophilia due to congenital protein C deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 483 total — 40 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000312

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9451
Approved symbol	PROC
Name	protein C, inactivator of coagulation factors Va and VIIIa
Location	2q14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000115718
Ensembl biotype	protein_coding
OMIM	612283
Entrez	5624

Gene structure

Transcript identifiers

Ensembl transcripts: 78 — 74 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000234071, ENST00000402125, ENST00000409048, ENST00000419985, ENST00000427769, ENST00000429925, ENST00000431364, ENST00000442644, ENST00000464089, ENST00000474030, ENST00000883837, ENST00000883838, ENST00000883839, ENST00000883840, ENST00000883841, ENST00000883842, ENST00000883843, ENST00000883844, ENST00000883845, ENST00000883846, ENST00000883847, ENST00000883848, ENST00000883849, ENST00000883850, ENST00000883851, ENST00000883852, ENST00000883853, ENST00000883854, ENST00000883855, ENST00000883856, ENST00000883857, ENST00000883858, ENST00000883859, ENST00000883860, ENST00000883861, ENST00000883862, ENST00000883863, ENST00000883864, ENST00000883865, ENST00000883866, ENST00000883867, ENST00000883868, ENST00000883869, ENST00000883870, ENST00000883871, ENST00000883872, ENST00000883873, ENST00000883874, ENST00000883875, ENST00000883876, ENST00000883877, ENST00000883878, ENST00000883879, ENST00000883880, ENST00000883881, ENST00000883882, ENST00000883883, ENST00000883884, ENST00000883885, ENST00000883886, ENST00000883887, ENST00000883888, ENST00000883889, ENST00000883890, ENST00000883891, ENST00000883892, ENST00000883893, ENST00000883894, ENST00000883895, ENST00000883896, ENST00000883897, ENST00000883898, ENST00000883899, ENST00000883900, ENST00000883901, ENST00000883902, ENST00000883903, ENST00000883904

RefSeq mRNA: 12 — MANE Select: NM_000312 NM_000312, NM_001375602, NM_001375603, NM_001375604, NM_001375605, NM_001375606, NM_001375607, NM_001375608, NM_001375609, NM_001375610, NM_001375611, NM_001375613

CCDS: CCDS2145, CCDS92858

Canonical transcript exons

ENST00000234071 — 9 exons

Exon	Start	End
ENSE00000775729	127427105	127427222
ENSE00000775730	127426085	127426227
ENSE00000775732	127423034	127423171
ENSE00000857263	127419922	127420012
ENSE00001019181	127423274	127423408
ENSE00001853552	127428357	127429242
ENSE00003534324	127422917	127422941
ENSE00003618780	127421283	127421449
ENSE00003899562	127418427	127418492

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 99.31.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9216 / max 797.7874, expressed in 338 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22422	1.5437	43
22429	0.8690	255
22424	0.2347	16
22430	0.1046	31
22428	0.0606	25
22425	0.0425	9
22423	0.0280	6
22427	0.0228	8
22426	0.0156	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.31	gold quality
liver	UBERON:0002107	97.81	gold quality
adult mammalian kidney	UBERON:0000082	80.41	gold quality
metanephros cortex	UBERON:0010533	76.08	gold quality
nephron tubule	UBERON:0001231	75.88	silver quality
kidney	UBERON:0002113	75.52	gold quality
kidney epithelium	UBERON:0004819	73.73	silver quality
cortex of kidney	UBERON:0001225	73.34	gold quality
triceps brachii	UBERON:0001509	73.19	gold quality
gluteal muscle	UBERON:0002000	73.06	gold quality
mucosa of transverse colon	UBERON:0004991	72.33	gold quality
pancreatic ductal cell	CL:0002079	71.93	silver quality
parotid gland	UBERON:0001831	71.56	gold quality
renal glomerulus	UBERON:0000074	71.03	silver quality
metanephric glomerulus	UBERON:0004736	69.10	silver quality
body of stomach	UBERON:0001161	68.28	gold quality
metanephros	UBERON:0000081	67.83	gold quality
granulocyte	CL:0000094	67.16	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	66.67	gold quality
lower esophagus mucosa	UBERON:0035834	65.88	gold quality
stomach	UBERON:0000945	65.76	gold quality
medial globus pallidus	UBERON:0002477	63.64	gold quality
fundus of stomach	UBERON:0001160	63.61	gold quality
transverse colon	UBERON:0001157	63.41	gold quality
nasal cavity epithelium	UBERON:0005384	63.19	gold quality
gall bladder	UBERON:0002110	63.09	gold quality
popliteal artery	UBERON:0002250	62.37	gold quality
tibial artery	UBERON:0007610	62.32	gold quality
descending thoracic aorta	UBERON:0002345	62.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	61.94	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	13.77
E-MTAB-5061	no	3.18
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXM1, HNF1A, NFIA, NFIC, ONECUT1, SMAD6, SP1

miRNA regulators (miRDB)

13 targeting PROC, 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-3910	99.95	71.13	2227
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-4317	98.49	67.09	987
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-6502-5P	98.09	66.73	495
HSA-MIR-1301-5P	98.09	66.62	495
HSA-MIR-3907	96.76	65.04	662
HSA-MIR-3059-3P	96.71	67.08	606
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-4653-3P	96.26	67.03	725
HSA-MIR-764	94.16	64.85	656

Literature-anchored findings (GeneRIF, showing 40)

• A heterozygous G–>T transversion at position 1388 of the protein C (PC) gene which predicted the substitution of Arg(-1) to a Leu (PC(R-1L)) was identified in a thrombophilic patient. This shifts the propeptidase cleavage site by one amino acid. (PMID:11686318)
• The combined effect of aprotinin and extracorporeal circulation resulted in lowered APC ratios for Factor V Leiden blood. Increased risk of perioperative thrombosis in cardiac surgical patients heterozygous for the F5L mutation is predicted. (PMID:11761087)
• Contribution of basic residues of the 70-80-loop to heparin binding and anticoagulant function of activated protein C. (PMID:11994010)
• X-ray crystallography of Activated Protein C (PMID:12029084)
• protease activated receptor 1 (PAR1) is the target for endothelial cell protein C receptor (EPCR)-dependent activated protein C (APC) signaling, suggesting a role for this receptor cascade in protection from sepsis (PMID:12052963)
• identifies FVa binding site in the positive exosite of APC that is primarily involved in binding and cleaving at Arg(506) on FVa (PMID:12063259)
• In this population-based study, a low protein C level has been determined to be associated with an increased incidence of venous thromboembolism. (PMID:12067914)
• APC is able to cleave at Arg506 and at Arg679 in FVa Cambridge and FVa Hong Kong. (PMID:12091344)
• Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces. (PMID:12091346)
• Molecular biological basis and diagnosis of hereditary defects (review) (PMID:12193972)
• APC inhibited both the binding of NF-kB to target sites and the degradation of I kappa B alpha, and inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. (PMID:12195699)
• activation of protein C by thrombin and inactivation of plasma FVa by APC are not impaired in human volunteers with acute hyperhomocysteinemia. (PMID:12200374)
• thrombomodulin-dependent activation of protein C is regulated by Smad6 and Smad7 (PMID:12407115)
• Smoking-induced vascular endothelium injury reduces activated protein C in a cigarette smoke dose-dependent manner, leading to activated protein C deficiency hypercoagulability. (PMID:12482406)
• The ability of activated protein C to upregulate the production of MCP-1 is most likely by increasing the stability of MCP-1-mRNA rather than by transcriptional activation via NF-KB (PMID:12540965)
• Data show that activated protein C directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53. (PMID:12563316)
• Interactions within thrombin that involve autolytic loop-2 and the Na(+)-binding site impair thrombin action on protein C, yet the activity of the mutant meizothrombins for protein C was increased to >10 times that of alpha-thrombin (PMID:12588872)
• physiologically relevant concentrations of PF4 stimulate thrombin-dependent activated protein C generation in cultured vascular endothelial cells (PMID:12609838)
• mAb identifies binding site on PROC involved in APC-mediated inactivation of factor Va; binding is phospholipid-independent and calcium-dependent. (PMID:12871399)
• seven newly found mutations in PROC are described; one with 4% PROC activity is a novel mutation in the promoter region, located in the HNF-1 site and associated with the Y226H heterozygous mutation (PMID:12960605)
• REVIEW OF the physiology of the protein C pathway with special emphasis on pediatric venous thromboembolism as well as acquired disturbances of protein C pathway during sepsis (PMID:14517747)
• activated protein C inactivates factor Va in the absence of arginine cleavage sites (PMID:14660667)
• The cleavage and inactivation of PAI-1 by generated thrombin is proposed to be responsible for the shortening of clot lysis time by Ca2+ and for coagulation-associated over-expression of fibrinolysis, which was suppressed by aPC. (PMID:14675098)
• free APC, APC-PCI and APC-alpha1AT generation is reduced in newborn compared to adult plasma with or without endothelium, likely due to reduced plasma PC levels. Endothelium enhances APC generation, regardless of plasma type. (PMID:14961149)
• Poor susceptibility to APC and impaired APC cofactor activity contributed equally to FV(Leiden)-associated APC resistance, whereas FV(R2)-associated APC resistance was entirely due to the reduced APC cofactor activity of FV(R2). (PMID:14976057)
• R147W mutation is a significant thrombotic risk factor and is the most common defect of PROC gene in Taiwanese patients with protein C deficiency (PMID:15114590)
• individuals carrying the 4600AG EPCR genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism (PMID:15116250)
• Review. TM, APC, & EPCR impact coagulation, inflammation, fibrinolysis, & cell proliferation. We review the functions of this complex multimolecular system & how its components maintain homeostasis under hypercoagulable &/or proinflammatory conditions. (PMID:15178554)
• Activated protein C (APC) and MMP-2 are coordinately up-regulated and tightly bound in rheumatoid arthritis (RA) synovial fluid and colocalized in synovia. APC may modulate MMP-2 activity in RA. (PMID:15248212)
• face 1 was necessary for efficient phospholipid binding but face 2 residues were not strictly required for phospholipid binding and were involved in the interaction with activated protein C (PMID:15308562)
• No significant differences exist between survivors and nonsurvivors of sepsis with respect to baseline protein C levels. (PMID:15319291)
• Results provide insights into the importance of the activated protein C (APC)-phospholipid interaction for the APC-mediated cleavages at Arg-306 and Arg-506 in coagulation factor Va. (PMID:15337738)
• Exposure of human umbilical vein endothelial cells or monocytes to activated protein C (6.25-100 nM) results in the release of endothelial protein C receptor-containing microparticles. (PMID:15486064)
• A new antiinflammatory mechanism of APC-dependent gene regulation occurs in human coronary artery endothelial cells. APC downregulates genes related to inflammation, most pronounced under intermediate or mild inflammatory conditions. (PMID:15505101)
• mechanism of thrombomodulin action is to kinetically facilitate the productive encounter of thrombin and protein C and to allosterically change the conformation of the activation peptide of protein C for optimal presentation to the thrombin active site (PMID:15582990)
• protein C binding to sEPCR and phospholipids is broadly dependent on correct Gla domain folding, but can be selectively influenced by judicious mutation (PMID:15634335)
• analysis of PAR1 cleavage and signaling in response to activated protein C and thrombin (PMID:15665002)
• APC anticoagulant activity in plasma and factor Va inactivation as a result of cleavages at R506 and R306 by APC is markedly enhanced by cholesterol in phospholipid vesicles (PMID:15670041)
• PC interactions with thrombin and thrombomodulin are likely contribute in a secondary or minor way to protein substrate affinity (PMID:15705565)
• endothelial protein C receptor ligation and sphingosine 1-phosphate receptor transactivation results in endothelial cell cytoskeletal rearrangement and barrier protection through activated protein C (PMID:15710622)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	proca	ENSDARG00000038258
danio_rerio	proca	ENSDARG00000093079
rattus_norvegicus	Proc	ENSRNOG00000014376
drosophila_melanogaster	CG9672	FBGN0030777

Paralogs (1): PROZ (ENSG00000126231)

Protein

Protein identifiers

Vitamin K-dependent protein C — P04070 (reviewed: P04070)

Alternative names: Anticoagulant protein C, Autoprothrombin IIA, Blood coagulation factor XIV

All UniProt accessions (7): E7END6, P04070, E7ENR9, E7EU72, E7EVH6, F2Z2A0, H7BYX9

UniProt curated annotations — full annotation on UniProt →

Function. Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids. Exerts a protective effect on the endothelial cell barrier function.

Subunit / interactions. Synthesized as a single chain precursor, which is cleaved into a light chain and a heavy chain held together by a disulfide bond. The enzyme is then activated by thrombin, which cleaves a tetradecapeptide from the amino end of the heavy chain; this reaction, which occurs at the surface of endothelial cells, is strongly promoted by thrombomodulin. Interacts (activated) with iripin-8, a serine protease inhibitor from Ixodes ricinus saliva.

Subcellular location. Secreted. Golgi apparatus. Endoplasmic reticulum.

Tissue specificity. Plasma; synthesized in the liver.

Post-translational modifications. Carboxylated by vitamin K-dependent GGCX to form gamma-carboxyglutamate; these residues are essential for the binding of calcium. N- and O-glycosylated. Partial (70%) N-glycosylation of Asn-371 with an atypical N-X-C site produces a higher molecular weight form referred to as alpha. The lower molecular weight form, not N-glycosylated at Asn-371, is beta. O-glycosylated with core 1 or possibly core 8 glycans. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains. May be phosphorylated on a Ser or Thr in a region (AA 25-30) of the propeptide.

Disease relevance. Thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860] A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency. The disease is caused by variants affecting the gene represented in this entry. Thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304] A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Calcium also binds, with stronger affinity to another site, beyond the GLA domain. This GLA-independent binding site is necessary for the recognition of the thrombin-thrombomodulin complex.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P04070-1	1	yes
P04070-2	2

RefSeq proteins (12): NP_000303, NP_001362531, NP_001362532, NP_001362533, NP_001362534, NP_001362535, NP_001362536, NP_001362537, NP_001362538, NP_001362539, NP_001362540, NP_001362542 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000294	GLA_domain	Domain
IPR000742	EGF	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR012224	Pept_S1A_FX	Family
IPR017857	Coagulation_fac-like_Gla_dom	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR043504
IPR050442	Peptidase_S1_coag_factors	Family

Pfam: PF00089, PF00594, PF14670

Enzyme classification (BRENDA):

• EC 3.4.21.69 — activated protein C (thrombin-activated peptidase) (BRENDA: 5 organisms, 241 substrates, 99 inhibitors, 42 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
S-2288	0.39–1.723	8
S-2366	0.0009–0.001	5
SPECTROZYME PCA	0.131–0.177	5
SPPCA	0.234–0.258	3
FACTOR VIIIA	0.0001	2
NALPHA-BENZOYL-L-ARGININE 4-NITROANILIDE	0.43–0.9	2
BENZYLOXYCARBONYL-VAL-GLY-ARG	0.528	1
D-ILE-PRO-ARG	0.606	1
D-PHE-PIPECOLYL-ARG	0.373	1
D-PRO-PHE-ARG	0.505	1
D-VAL-CYCLOHEXYL-ALA-ARG	0.259	1
D-VAL-LEU-ARG	0.345	1
FACTOR VA	—	1
FACTOR VAR506Q	0.0002	1
MEMBRANE-BOUND FACTOR VA	—	1

UniProt features (177 total): sequence variant 93, strand 25, disulfide bond 12, modified residue 11, helix 9, glycosylation site 5, turn 4, domain 4, active site 3, chain 3, sequence conflict 2, splice variant 2, signal peptide 1, propeptide 1, site 1, peptide 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
1LQV	X-RAY DIFFRACTION	1.6
3JTC	X-RAY DIFFRACTION	1.6
4DT7	X-RAY DIFFRACTION	1.9
6M3B	X-RAY DIFFRACTION	2.2
1AUT	X-RAY DIFFRACTION	2.8
3F6U	X-RAY DIFFRACTION	2.8
9MOV	ELECTRON MICROSCOPY	3
9MOT	ELECTRON MICROSCOPY	3.15
8JRV	ELECTRON MICROSCOPY	3.3
9BVM	ELECTRON MICROSCOPY	3.4
8JRU	ELECTRON MICROSCOPY	3.5
6M3C	X-RAY DIFFRACTION	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04070-F1	82.35	0.58

Antibody-complex structures (SAbDab): 2 — 6M3B, 6M3C

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 253 (charge relay system); 299 (charge relay system); 402 (charge relay system); 211–212 (cleavage; by thrombin)

Post-translational modifications (11): 48, 49, 56, 58, 61, 62, 67, 68, 71, 113, 347

Disulfide bonds (12): 59–64, 92–111, 101–106, 105–120, 122–131, 140–151, 147–160, 162–175, 183–319, 238–254, 373–387, 398–426

Glycosylation sites (5): 19, 139, 290, 355, 371

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-159740	Gamma-carboxylation of protein precursors
R-HSA-159763	Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus
R-HSA-159782	Removal of aminoterminal propeptides from gamma-carboxylated proteins
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9769733	Fibrin formation
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9769743	Amplification and propagation of coagulation cascade
R-HSA-9930449	Defective cleavage of FV variant at a.a.534
R-HSA-9930479	Defective cleavage of FV variant at R334
R-HSA-140837
R-HSA-140875

MSigDB gene sets: 202 (showing top): MODULE_172, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_COAGULATION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GNF2_GSTM1, PEREZ_TP63_TARGETS, GNF2_HPN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, MODULE_16, FOXD3_01, GOBP_NEGATIVE_REGULATION_OF_COAGULATION

GO Biological Process (8): proteolysis (GO:0006508), blood coagulation (GO:0007596), negative regulation of blood coagulation (GO:0030195), negative regulation of apoptotic process (GO:0043066), negative regulation of inflammatory response (GO:0050728), negative regulation of coagulation (GO:0050819), positive regulation of establishment of endothelial barrier (GO:1903142), hemostasis (GO:0007599)

GO Molecular Function (7): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), Golgi lumen (GO:0005796)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	3
Coagulation pathway	3
Defective FV causes thrombophilia	2
Hemostasis	1
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
coagulation	2
peptidase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
intracellular organelle lumen	2
protein metabolic process	1
hemostasis	1
wound healing	1
blood coagulation	1
regulation of blood coagulation	1
negative regulation of coagulation	1
negative regulation of wound healing	1
negative regulation of hemostasis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
regulation of coagulation	1
negative regulation of multicellular organismal process	1
establishment of endothelial barrier	1
positive regulation of endothelial cell development	1
regulation of establishment of endothelial barrier	1
regulation of body fluid levels	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
endoplasmic reticulum	1
Golgi apparatus	1

Protein interactions and networks

STRING

1416 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PROC	THBD	P07204	923
PROC	PROCR	Q9UNN8	846
PROC	F3	P13726	803
PROC	PGA4	P00790	800
PROC	PGA4	P00790	796
PROC	PGA4	P00790	784
PROC	SERPINC1	P01008	771
PROC	SPINK1	P00995	653
PROC	PGC	P20142	649
PROC	TFPI	P10646	629
PROC	F2R	P25116	620
PROC	F8	P00451	619
PROC	F13B	P05160	616
PROC	CPB2	Q96IY4	609
PROC	NUP85	Q9BW27	560

IntAct

13 interactions, top by confidence:

A	B	Type	Score
CYSRT1	PROC	psi-mi:“MI:0915”(physical association)	0.560
NPB	CST4	psi-mi:“MI:0914”(association)	0.530
MMP15	PROC	psi-mi:“MI:0915”(physical association)	0.400
PROC	MMP15	psi-mi:“MI:0915”(physical association)	0.400
PROC	MATR3	psi-mi:“MI:0915”(physical association)	0.400
CSNK2B	PROC	psi-mi:“MI:0915”(physical association)	0.370
PROC	TK1	psi-mi:“MI:0915”(physical association)	0.370
NPB	IL16	psi-mi:“MI:0914”(association)	0.350
PROC	PROS1	psi-mi:“MI:0914”(association)	0.350
PROC	WNT5A	psi-mi:“MI:0914”(association)	0.350
PROC	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): EPHA6 (Affinity Capture-MS), PROC (Affinity Capture-MS), UQCRH (Affinity Capture-MS), PDF (Affinity Capture-MS), PROS1 (Affinity Capture-MS), WNT5A (Affinity Capture-MS), CYSRT1 (Two-hybrid), PROC (Reconstituted Complex), PROC (Reconstituted Complex), MATR3 (Proximity Label-MS), PROC (Reconstituted Complex), PROCR (Reconstituted Complex), SERPINA5 (Co-purification), WNT5A (Affinity Capture-MS), PROC (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVH4, A1L453, A4D1T9, A6H6T1, A8MTI9, A8QL53, A8QL57, B5U6Y3, E5RG02, O35453, O70169, P00745, P04070, P08709, P0CG03, P0DJE9, P22891, Q14BX2, Q28278, Q28661, Q2F9P2, Q2F9P4, Q2TV78, Q3V0Q7, Q402U7, Q4R7Y7, Q5FBW1, Q5M8S2, Q6AXZ6, Q6AY28, Q6IE62, Q6IE63, Q6PEW0, Q6UWB4, Q76HL1, Q7M756, Q7M761, Q7RTY5, Q7RTY7, Q7Z5A4

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

8 interactions.

A	Effect	B	Mechanism
Thrombin-Thrombomodulin	“up-regulates activity”	PROC	cleavage
PROC	“down-regulates activity”	F7	cleavage
PROC	“down-regulates activity”	F5	cleavage
GGCX	“up-regulates activity”	PROC	carboxylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	51
Uncertain significance	189
Likely benign	108
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048662	NM_000312.4(PROC):c.400+2T>C	Pathogenic
1068737	NM_000312.4(PROC):c.561G>A (p.Trp187Ter)	Pathogenic
1073999	NM_000312.4(PROC):c.400G>T (p.Glu134Ter)	Pathogenic
1074000	NM_000312.4(PROC):c.520C>T (p.Gln174Ter)	Pathogenic
1389677	NM_000312.4(PROC):c.445dup (p.His149fs)	Pathogenic
1420279	NM_000312.4(PROC):c.675G>A (p.Trp225Ter)	Pathogenic
1427775	NM_000312.4(PROC):c.1218G>A (p.Met406Ile)	Pathogenic
1676815	NM_000312.4(PROC):c.151C>T (p.Arg51Cys)	Pathogenic
1976706	NM_000312.4(PROC):c.698dup (p.Lys234fs)	Pathogenic
1992373	NM_000312.4(PROC):c.94C>T (p.Arg32Cys)	Pathogenic
2203144	NM_000312.4(PROC):c.560G>A (p.Trp187Ter)	Pathogenic
2700349	NM_000312.4(PROC):c.6G>A (p.Trp2Ter)	Pathogenic
2734266	NM_000312.4(PROC):c.400+5G>T	Pathogenic
3247344	NC_000002.11:g.(?128175983)(128184818_?)del	Pathogenic
3380947	NM_000312.4(PROC):c.373G>T (p.Gly125Cys)	Pathogenic
3573001	NM_000312.4(PROC):c.360C>A (p.Cys120Ter)	Pathogenic
3716585	NM_000312.4(PROC):c.400+2T>A	Pathogenic
3720362	NM_000312.4(PROC):c.400+5G>A	Pathogenic
4292624	NM_000312.4(PROC):c.715_724del (p.Gly239fs)	Pathogenic
4540676	NM_000312.4(PROC):c.1330T>C (p.Trp444Arg)	Pathogenic
4698752	NM_000312.4(PROC):c.1115dup (p.Cys373fs)	Pathogenic
4734045	NM_000312.4(PROC):c.714C>A (p.Cys238Ter)	Pathogenic
4735017	NM_000312.4(PROC):c.318C>A (p.Cys106Ter)	Pathogenic
522437	NM_000312.4(PROC):c.340G>T (p.Gly114Cys)	Pathogenic
579309	NM_000312.4(PROC):c.1019C>T (p.Thr340Met)	Pathogenic
656	NM_000312.4(PROC):c.1042C>T (p.Arg348Ter)	Pathogenic
657	NM_000312.4(PROC):c.1332G>C (p.Trp444Cys)	Pathogenic
658	PROC, ARG12TRP	Pathogenic
661205	NM_000312.4(PROC):c.400+1G>A	Pathogenic
663	NM_000312.4(PROC):c.1027G>A (p.Gly343Ser)	Pathogenic

SpliceAI

1612 predictions. Top by Δscore:

Variant	Effect	Δscore
2:127418493:G:GG	donor_gain	1.0000
2:127421424:A:T	donor_gain	1.0000
2:127421450:G:GG	donor_gain	1.0000
2:127426194:G:GT	donor_gain	1.0000
2:127426194:G:T	donor_gain	1.0000
2:127427192:GA:G	donor_gain	1.0000
2:127428353:GCA:G	acceptor_loss	1.0000
2:127428354:CA:C	acceptor_loss	1.0000
2:127428355:A:AC	acceptor_loss	1.0000
2:127428355:A:AG	acceptor_gain	1.0000
2:127428355:AG:A	acceptor_gain	1.0000
2:127428356:G:GC	acceptor_gain	1.0000
2:127428356:GG:G	acceptor_gain	1.0000
2:127428356:GGA:G	acceptor_gain	1.0000
2:127428356:GGAGA:G	acceptor_gain	1.0000
2:127421414:G:GT	donor_gain	0.9900
2:127421423:G:GT	donor_gain	0.9900
2:127422915:A:AG	acceptor_gain	0.9900
2:127422915:AGCT:A	acceptor_gain	0.9900
2:127422916:G:GA	acceptor_gain	0.9900
2:127422916:GCT:G	acceptor_gain	0.9900
2:127422916:GCTG:G	acceptor_gain	0.9900
2:127423032:AGAC:A	acceptor_gain	0.9900
2:127423033:GACG:G	acceptor_gain	0.9900
2:127423128:C:G	donor_gain	0.9900
2:127423167:GCGCG:G	donor_gain	0.9900
2:127423169:GCG:G	donor_gain	0.9900
2:127423406:CAG:C	donor_loss	0.9900
2:127423407:AG:A	donor_loss	0.9900
2:127423408:GGTGA:G	donor_loss	0.9900

AlphaMissense

3068 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:127428719:T:A	C387S	0.999
2:127428720:G:C	C387S	0.999
2:127428586:G:C	W342C	0.998
2:127428586:G:T	W342C	0.998
2:127428677:T:A	C373S	0.998
2:127428678:G:C	C373S	0.998
2:127427187:G:A	C254Y	0.997
2:127427188:C:G	C254W	0.997
2:127428456:A:C	D299A	0.997
2:127428456:A:T	D299V	0.997
2:127428461:G:C	A301P	0.997
2:127428584:T:A	W342R	0.997
2:127428584:T:C	W342R	0.997
2:127428719:T:C	C387R	0.997
2:127428821:A:C	S421R	0.997
2:127428823:C:A	S421R	0.997
2:127428823:C:G	S421R	0.997
2:127426222:T:A	W225R	0.996
2:127426222:T:C	W225R	0.996
2:127427172:T:C	L249P	0.996
2:127427186:T:A	C254S	0.996
2:127427187:G:C	C254S	0.996
2:127428677:T:C	C373R	0.996
2:127428720:G:A	C387Y	0.996
2:127428836:T:A	C426S	0.996
2:127428837:G:C	C426S	0.996
2:127428892:G:C	W444C	0.996
2:127428892:G:T	W444C	0.996
2:127427186:T:C	C254R	0.995
2:127428465:T:C	L302P	0.995

dbSNP variants (sampled 300 via entrez): RS1000579280 (2:127420992 A>T), RS1001119152 (2:127420719 C>G), RS1001440831 (2:127429392 G>A), RS1001540779 (2:127427880 A>T), RS1001550189 (2:127421065 G>A), RS1001557004 (2:127417571 T>G), RS1001565169 (2:127423200 C>A,G), RS1001567406 (2:127423731 C>G,T), RS1001643154 (2:127429140 T>C), RS1002153486 (2:127417800 C>A), RS1002572117 (2:127422470 A>T), RS1002601049 (2:127418341 G>T), RS1002756062 (2:127424250 A>T), RS1003145088 (2:127418074 A>C), RS1003224488 (2:127422524 A>G,T)

Disease associations

OMIM: gene MIM:612283 | disease phenotypes: MIM:176860, MIM:612304

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombophilia due to protein C deficiency, autosomal dominant	Definitive	Autosomal dominant
hereditary thrombophilia due to congenital protein C deficiency	Definitive	Semidominant
thrombophilia due to protein C deficiency, autosomal recessive	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary thrombophilia due to congenital protein C deficiency	Definitive	SD

Mondo (5): thrombophilia due to protein C deficiency, autosomal dominant (MONDO:0008316), thrombophilia due to protein C deficiency, autosomal recessive (MONDO:0012860), hereditary thrombophilia due to congenital protein C deficiency (MONDO:0019145), cerebral palsy (MONDO:0006497), hereditary angioedema with normal C1Inh (MONDO:0100567)

Orphanet (2): Severe hereditary thrombophilia due to congenital protein C deficiency (Orphanet:745), Hereditary angioedema with normal C1Inh (Orphanet:528647)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000478	Abnormality of the eye
HP:0000707	Abnormality of the nervous system
HP:0000963	Thin skin
HP:0000979	Purpura
HP:0001000	Abnormality of skin pigmentation
HP:0001038	Warfarin-induced skin necrosis
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0002204	Pulmonary embolism
HP:0002625	Deep venous thrombosis
HP:0002638	Superficial thrombophlebitis
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0004850	Recurrent deep vein thrombosis
HP:0004936	Venous thrombosis
HP:0005293	Venous insufficiency
HP:0005305	Cerebral venous thrombosis
HP:0005543	Reduced protein C activity
HP:0007902	Vitreous hemorrhage
HP:0008065	Aplasia/Hypoplasia of the skin
HP:0100021	Cerebral palsy
HP:0100659	Abnormal cerebral vascular morphology
HP:0100724	Hypercoagulability
HP:0100758	Gangrene

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000780_2	Protein C levels	4.000000e-36
GCST002686_1	Protein C levels	2.000000e-12
GCST006119_6	Protein C levels	2.000000e-42
GCST006585_105	Blood protein levels	2.000000e-12
GCST006585_1073	Blood protein levels	5.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004633	protein C measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D020151	Protein C Deficiency	C15.378.100.100.690; C15.378.147.880; C15.378.925.795; C16.320.099.690
C535424	Congenital thrombotic disease, due to Protein C deficiency (supp.)
C567353	Thrombophilia, Hereditary, Due To Protein C Deficiency, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4444 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 18,864 (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
CHEMBL266349	MELAGATRAN	4	5,421
CHEMBL48361	DABIGATRAN	3	13,443

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1799808	Dosage	3	phenprocoumon

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1799808	PROC	3	1.75	1	phenprocoumon
rs1799809	PROC		0.00	0
rs2069919	PROC		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 37 [PMID: 24418773]	Inhibition	7.4	pKi

Binding affinities (BindingDB)

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

Ligand	Measure	Value	Patent
(2R)-N-[(3-aminobenzene)sulfonyl]-2-[(4-carbamimidoyl-3-hydroxyphenyl)amino]-2-(3,5-diethoxy-2-fluorophenyl)acetamide	KI	0.35 nM
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-pyridin-4-ylbutanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	20 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-piperidin-4-ylbutanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	90 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-oxidopyridin-1-ium-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	120 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-piperidin-4-ylpentanamide	KI	300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-(1-oxidopyridin-1-ium-4-yl)pentanamide	KI	400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 4-[(4R)-4-(benzylsulfonylamino)-5-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-5-oxopentyl]piperidine-1-carboxylate	KI	400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
BDBM108100	KI	750 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-pyridin-4-ylpentanamide	KI	850 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-phenylpentanamide	KI	1100 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(2-methoxyacetyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1600 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-2-phenylacetyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1600 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]-N-methylpiperidine-1-carboxamide	KI	1700 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-4-(1-acetylpiperidin-4-yl)-2-(benzylsulfonylamino)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1900 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]piperidine-1-carboxylate	KI	2000 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-butanoylpiperidin-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2200 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(cyclopropanecarbonyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-propanoylpiperidin-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	KI	2400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-(tetrazol-1-yl)pentanamide	KI	2400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]-N,N-dimethylpiperidine-1-carboxamide	KI	2500 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(2-methylpropanoyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	3200 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoate	KI	5900 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use

ChEMBL bioactivities

129 potent at pChembl≥5 of 179 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.34	Ki	0.46	nM	CHEMBL4471466
9.21	Ki	0.61	nM	CHEMBL2016865
8.72	Ki	1.9	nM	CHEMBL4638245
8.29	Ki	5.1	nM	CHEMBL2016866
7.57	Ki	27	nM	CHEMBL3660179
7.41	Ki	39	nM	CHEMBL2315240
7.41	Ki	39	nM	CHEMBL3898956
7.40	Ki	40	nM	CHEMBL3115901
7.39	Ki	41	nM	CHEMBL3594313
7.32	Ki	48	nM	CHEMBL2016869
7.22	Ki	60	nM	CHEMBL3660177
7.16	Ki	70	nM	CHEMBL3898371
7.14	Ki	73	nM	CHEMBL3127463
7.05	Ki	90	nM	CHEMBL2016871
7.00	Ki	100	nM	CHEMBL3115900
7.00	Ki	100	nM	CHEMBL3115904
7.00	IC50	100	nM	CHEMBL211973
6.89	IC50	130	nM	CHEMBL3115901
6.81	Ki	155	nM	CHEMBL3956096
6.76	Ki	175	nM	CHEMBL3967204
6.72	Ki	190	nM	CHEMBL3902498
6.70	Ki	200	nM	CHEMBL3115897
6.68	Ki	210	nM	CHEMBL3660187
6.66	Ki	220	nM	CHEMBL3934882
6.65	Ki	223	nM	CHEMBL2016870
6.60	IC50	250	nM	CHEMBL215639
6.60	Ki	250	nM	CHEMBL3660188
6.58	IC50	260	nM	CHEMBL3115900
6.52	Ki	300	nM	CHEMBL3115903
6.52	Ki	300	nM	CHEMBL3115899
6.52	Ki	300	nM	CHEMBL3115898
6.52	Ki	300	nM	CHEMBL3115894
6.51	Ki	310	nM	CHEMBL3660171
6.47	Ki	340	nM	CHEMBL3984725
6.46	IC50	350	nM	CHEMBL425613
6.40	Ki	400	nM	CHEMBL3115893
6.40	Ki	400	nM	CHEMBL3660173
6.38	Ki	420	nM	CHEMBL2315242
6.37	IC50	430	nM	CHEMBL215357
6.33	IC50	470	nM	CHEMBL3115904
6.30	Ki	500	nM	CHEMBL3115905
6.30	Ki	500	nM	CHEMBL215295
6.26	Ki	555	nM	CHEMBL3660186
6.25	Ki	564	nM	CHEMBL2016868
6.24	Ki	570	nM	CHEMBL3660190
6.22	Ki	600	nM	CHEMBL3660191
6.17	IC50	670	nM	CHEMBL3115897
6.15	IC50	710	nM	CHEMBL212789
6.14	Ki	725	nM	CHEMBL3900166
6.12	IC50	750	nM	CHEMBL380157

PubChem BioAssay actives

107 with measured affinity, of 468 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)-3-[3-(aminomethyl)phenyl]-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	1558649: Inhibition of activated protein kinase C (unknown origin)	ki	0.0005	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	656104: Inhibition of activated protein C by dixon plot method	ki	0.0006	uM
methyl 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	1657779: Inhibition of human activated protein C using pyro-Glu-Pro-Arg-pNA(para-nitroaniline) substrate by spectrophotometry	ki	0.0019	uM
(7S,10R)-10-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-4,9,13-trioxo-3,8,14-triazabicyclo[14.3.1]icosa-1(19),16(20),17-triene-7-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.0051	uM
(11S,14R)-14-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,13,22-trioxo-1,4,12,21,24-pentazatetracyclo[22.2.2.15,9.116,20]triaconta-5,7,9(30),16(29),17,19-hexaene-11-carboxamide;2,2,2-trifluoroacetic acid	724897: Inhibition of human activated protein C using H-D-Lys(Cbz)-Pro-Arg-pNA as substrate after 5 to 10 mins by micro plate reader analysis	ki	0.0390	uM
(5R,11R)-11-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-16-cyclopropylsulfonyl-7-(2,2-difluoroethoxy)-5,13-dimethyl-2,13-diazatricyclo[13.3.1.16,10]icosa-1(19),6,8,10(20),15,17-hexaene-3,12-dione	1331378: Inhibition of activated protein C (unknown origin)	ki	0.0390	uM
2-[[(2R)-1-[[(2S)-3-(4-aminophenyl)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.0400	uM
4-[[(2R)-7-ethylsulfonyl-3,12-dioxo-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-yl]amino]benzenecarboximidamide	1235265: Inhibition of human APC measured for 30 mins	ki	0.0410	uM
(12S,15R)-15-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,14,24-trioxo-1,4,13,23,26-pentazatetracyclo[24.2.2.16,10.117,21]dotriaconta-6,8,10(32),17(31),18,20-hexaene-12-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.0480	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclopropane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.0700	uM
2-[3-(6-carbamimidoyl-4-methyl-4-phenyl-2,3-dihydro-1H-quinolin-2-yl)-5-(3-methylbutanoylamino)phenyl]-5-carbamoylbenzoic acid	1074188: Binding affinity to human activated protein C assessed as release of p-nitroaniline after 10 to 120 mins by spectrophotometric analysis	ki	0.0730	uM
(2R)-N-(3-aminophenyl)sulfonyl-2-(4-carbamimidoyl-3-hydroxyanilino)-2-(3,5-diethoxy-2-fluorophenyl)acetamide	1797275: Serine Protease Inhibition Assay from Article 10.1074/jbc.M409068200: “A selective, slow binding inhibitor of factor VIIa binds to a nonstandard active site conformation and attenuates thrombus formation in vivo.”	ki	0.0870	uM
(13S,16R)-16-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-15-oxo-2,7-dioxa-14-azatricyclo[16.2.2.28,11]tetracosa-1(21),4,8,10,18(22),19,23-heptaene-13-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.0900	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.1000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.1000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.1000	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclohexane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.1550	uM
(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-7-[1-(2H-tetrazol-5-yl)cyclopropyl]-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.1750	uM
(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-7-cyclopropylsulfonyl-4,15,17-trimethyl-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1315785: Inhibition of human activated protein C using pyroGlu-Pro-Arg-pNA as substrate assessed as release of pNA after 10 to 120 mins by spectrophotometric method	ki	0.1900	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.2000	uM
(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-7-cyclopropyl-4,15,17-trimethyl-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.2200	uM
(21S,24R)-24-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-4,12,23-trioxo-3,13,22-triazatetracyclo[24.3.1.16,10.115,19]dotriaconta-1(29),6(32),7,9,15,17,19(31),26(30),27-nonaene-21-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.2230	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydrocyclopenta[a]naphthalen-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.2500	uM
2-[[(2R)-1-[[3-[4-(aminomethyl)phenyl]-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-naphthalen-1-yl-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
2-[[(2R)-1-[[1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclopentane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.3400	uM
2-[[(2R)-1-[[(1S)-2-[(4-carbamimidoylphenyl)methylamino]-1-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.3500	uM
2-[[(2R)-1-[[1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-3-piperidin-4-ylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.4000	uM
(18R,21S)-18-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,10,19-trioxo-2,5,8,11,20-pentazatetracyclo[21.2.2.25,8.112,16]triaconta-1(26),12,14,16(28),23(27),24-hexaene-21-carboxamide;2,2,2-trifluoroacetic acid	724897: Inhibition of human activated protein C using H-D-Lys(Cbz)-Pro-Arg-pNA as substrate after 5 to 10 mins by micro plate reader analysis	ki	0.4200	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydrophenalen-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.4300	uM
(2S)-2-[[(2R)-2-amino-2-cyclohexylacetyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-5-(diaminomethylideneamino)pentanamide	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.5000	uM
2-[[(1R)-2-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-1-cyclohexyl-2-oxoethyl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.5000	uM
(12S,15R)-15-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,14,24-trioxo-4,13,23-triazatetracyclo[24.2.2.16,10.117,21]dotriaconta-1(29),6,8,10(32),17(31),18,20,26(30),27-nonaene-12-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.5640	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.7100	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclobutane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.7250	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.7500	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.8000	uM
3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]propanoic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.8000	uM
(2R)-2-[(1-aminoisoquinolin-6-yl)amino]-7-ethylsulfonyl-17-methyl-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1235265: Inhibition of human APC measured for 30 mins	ki	0.8300	uM
(20S,23R)-23-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,12,22-trioxo-2,6,9,13,21-pentazatetracyclo[23.2.2.26,9.114,18]dotriaconta-1(28),14,16,18(30),25(29),26-hexaene-20-carboxamide;2,2,2-trifluoroacetic acid	724897: Inhibition of human activated protein C using H-D-Lys(Cbz)-Pro-Arg-pNA as substrate after 5 to 10 mins by micro plate reader analysis	ki	0.8800	uM
2-[[(2R)-2-amino-3-cyclohexylpropanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.9000	uM
2-[[(2R)-1-[[(1S)-2-[(4-carbamimidoylphenyl)methylamino]-2-oxo-1-piperidin-4-ylethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.9000	uM
2-[[(2R)-1-[[6-[(4-carbamimidoylphenyl)methylcarbamoyl]-5,7-dihydrocyclopenta[b]pyridin-6-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	1.0700	uM
2-[[(2R)-1-[[1-[(4-carbamimidoylphenyl)methylamino]-3-(4-cyanophenyl)-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	1.1000	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-4-methyl-1-oxohexan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	1.1200	uM
(11R)-11-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-16-cyclopropylsulfonyl-7-(2,2-difluoroethoxy)-13-methyl-2,13-diazatricyclo[13.3.1.16,10]icosa-1(19),6,8,10(20),15,17-hexaene-3,12-dione	1331378: Inhibition of activated protein C (unknown origin)	ki	1.2000	uM
3-[[(3S)-3-[(7-methoxynaphthalen-2-yl)sulfonylamino]-2-oxopyrrolidin-1-yl]methyl]benzenecarboximidamide	30725: Compound was evaluated for the inhibition of activated protein C (aPC)	ki	1.2000	uM
2-[[(1R)-2-[(2S)-2-[(4-carbamimidoylphenyl)methylcarbamoyl]azetidin-1-yl]-1-cyclohexyl-2-oxoethyl]amino]acetic acid	1069326: Inhibition of human APC using S-2366 as substrate preincubated for 300 seconds followed by substrate addition measured after 40 mins by spectrophotometric analysis	ic50	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
ethinyl estradiol-desogestrel combination	decreases expression, increases activity, increases expression, affects activity	8
Ethinyl Estradiol	affects binding, increases expression, affects cotreatment, increases activity, affects expression	7
Gestodene	decreases expression, affects cotreatment, affects expression, increases activity, increases expression (+1 more)	6
Valproic Acid	decreases expression, affects cotreatment, increases expression, affects expression	5
Cyclosporine	affects expression, decreases expression, increases expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
Benzo(a)pyrene	affects methylation, decreases expression	3
Contraceptives, Oral	affects activity, decreases expression, affects response to substance	3
Levonorgestrel	affects cotreatment, increases activity, increases expression	3
Particulate Matter	increases expression, decreases expression, increases abundance	3
Air Pollutants	increases abundance, increases expression, decreases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Warfarin	affects response to substance, increases response to substance	2
aristolochic acid I	increases expression	1
testosterone enanthate	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
norgestimate	affects cotreatment, increases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	decreases expression	1
dienogest	affects cotreatment, increases activity	1
cupric chloride	decreases reaction, affects binding, decreases activity	1
zinc sulfide	affects cotreatment, decreases expression	1
CycloProvera	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CMF protocol	decreases expression	1
brequinar	decreases expression	1

ChEMBL screening assays

117 unique, capped per target: 117 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008037	Binding	Inhibition of activated protein C	Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-chloroindole-7-yl-based factor Xa inhibitors. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	PHASE3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	PHASE3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A
NCT03306212	PHASE3	COMPLETED	Efficacy of Intermittent Serial Casting on Spastic Wrist Flexion Deformity