Target Information
Target General Information | Top | |||||
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Target ID |
T78890
(Former ID: TTDI02330)
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Target Name |
Tissue factor pathway inhibitor (TFPI)
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Synonyms |
TFPI1; Lipoprotein-associated coagulation inhibitor; LACI; Extrinsic pathway inhibitor; EPI
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Gene Name |
TFPI
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Christmas disease [ICD-11: 3B11] | |||||
2 | Coagulation defect [ICD-11: 3B10] | |||||
3 | Sepsis [ICD-11: 1G40-1G41] | |||||
Function |
It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma. Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex.
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UniProt ID | ||||||
Sequence |
MIYTMKKVHALWASVCLLLNLAPAPLNADSEEDEEHTIITDTELPPLKLMHSFCAFKADD
GPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRDNANRIIKTTLQQE KPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDGPN GFQVDNYGTQLNAVNNSLTPQSTKVPSLFEFHGPSWCLTPADRGLCRANENRFYYNSVIG KCRPFKYSGCGGNENNFTSKQECLRACKKGFIQRISKGGLIKTKRKRKKQRVKIAYEEIF VKNM Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
1 | Concizumab | Drug Info | Phase 3 | Haemophilia B | [2] | |
2 | PF-06741086 | Drug Info | Phase 3 | Hemophilia | [3] | |
3 | Tifacogin | Drug Info | Phase 3 | Sepsis | [1] | |
4 | BAX-499 | Drug Info | Phase 1 | Factor IX deficiency | [4] | |
5 | NN-7415 | Drug Info | Phase 1 | Factor IX deficiency | [5] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 3 Inhibitor drugs | + | ||||
1 | PF-06741086 | Drug Info | [7] | |||
2 | Tifacogin | Drug Info | [1] | |||
3 | BAX-499 | Drug Info | [8], [9] | |||
Modulator | [+] 1 Modulator drugs | + | ||||
1 | NN-7415 | Drug Info | [10] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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Complement and coagulation cascades | hsa04610 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy |
Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 3.45E-07 |
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Closeness centrality | 1.72E-01 | Radiality | 1.27E+01 | Clustering coefficient | 6.67E-01 |
Neighborhood connectivity | 6.33E+00 | Topological coefficient | 5.28E-01 | Eccentricity | 13 |
Download | Click to Download the Full PPI Network of This Target | ||||
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
1 | Complement and coagulation cascades | |||||
NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
1 | IL4 Signaling Pathway | |||||
2 | TGF_beta_Receptor Signaling Pathway | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | Blood coagulation | |||||
PID Pathway | [+] 1 PID Pathways | + | ||||
1 | Syndecan-4-mediated signaling events | |||||
Reactome | [+] 1 Reactome Pathways | + | ||||
1 | Extrinsic Pathway of Fibrin Clot Formation | |||||
WikiPathways | [+] 3 WikiPathways | + | ||||
1 | Complement and Coagulation Cascades | |||||
2 | Integrated Breast Cancer Pathway | |||||
3 | Formation of Fibrin Clot (Clotting Cascade) |
References | Top | |||||
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REF 1 | Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003 Jul 9;290(2):238-47. | |||||
REF 2 | ClinicalTrials.gov (NCT05135559) Open-label Study Investigating Efficacy, Safety and Pharmacokinetics of Concizumab Prophylaxis in Children Below 12 Years With Haemophilia A or B With or Without Inhibitors. U.S.National Institutes of Health. | |||||
REF 3 | ClinicalTrials.gov (NCT03938792) Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Patients With Severe Hemophilia A or B. U.S. National Institutes of Health. | |||||
REF 4 | ClinicalTrials.gov (NCT01191372) First-in-Human and Proof-of-Mechanism Study of ARC19499 Administered to Hemophilia Patients. U.S. National Institutes of Health. | |||||
REF 5 | ClinicalTrials.gov (NCT01228669) Safety of NNC 0172-0000-2021 in Healthy Male Subjects and Subjects With Haemophilia A or B. U.S. National Institutes of Health. | |||||
REF 6 | Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood. 2019 Nov 28;134(22):1973-1982. | |||||
REF 7 | Neutralizing Antibody Assay Development with High Drug and Target Tolerance to Support Clinical Development of an Anti-TFPI Therapeutic Monoclonal Antibody. AAPS J. 2019 Mar 29;21(3):46. | |||||
REF 8 | Aptamer BAX 499 mediates inhibition of tissue factor pathway inhibitor via interaction with multiple domains of the protein. J Thromb Haemost. 2013 Jun;11(6):1137-45. | |||||
REF 9 | Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma. J Thromb Haemost. 2012 Aug;10(8):1581-90. | |||||
REF 10 | Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.J Thromb Haemost.2015 May;13(5):743-54. |
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