Target Information
| Target General Information | Top | |||||
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| Target ID |
T72702
(Former ID: TTDR00396)
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| Target Name |
Tissue factor (F3)
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| Synonyms |
Thromboplastin; TF; F3; Coagulation factor III; CD142 antigen
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| Gene Name |
F3
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Cervical cancer [ICD-11: 2C77] | |||||
| Function |
Initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The [TF:VIIa] complex activates factors IX or X by specific limited protolysis. TF plays a role in normal hemostasis by initiating the cell-surface assemblyand propagation of the coagulation protease cascade.
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| UniProt ID | ||||||
| Sequence |
METPAWPRVPRPETAVARTLLLGWVFAQVAGASGTTNTVAAYNLTWKSTNFKTILEWEPK
PVNQVYTVQISTKSGDWKSKCFYTTDTECDLTDEIVKDVKQTYLARVFSYPAGNVESTGS AGEPLYENSPEFTPYLETNLGQPTIQSFEQVGTKVNVTVEDERTLVRRNNTFLSLRDVFG KDLIYTLYYWKSSSSGKKTAKTNTNEFLIDVDKGENYCFSVQAVIPSRTVNRKSTDSPVE CMGQEKGEFREIFYIIGAVVFVVIILVIILAISLHKCRKAGVGQSWKENSPLNVS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T17CZC | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Tisotumab vedotin | Drug Info | Approved | Cervical cancer | [2] | |
| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | ALT-836 | Drug Info | Phase 2 | Adult respiratory distress syndrome | [3] | |
| 2 | TT-173 | Drug Info | Phase 2 | Bleeding disorder | [4] | |
| 3 | MORAb-066 | Drug Info | Phase 1 | Pancreatic cancer | [5], [6] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | ALT-836 | Drug Info | [7] | |||
| 2 | D-Pro-Phe-Arg chloromethyl ketone | Drug Info | [9] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | TT-173 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Gamma-Carboxy-Glutamic Acid | Ligand Info | |||||
| Structure Description | Crystal structure of the super-active FVIIa variant VYT in complex with tissue factor | PDB:6R2W | ||||
| Method | X-ray diffraction | Resolution | 1.25 Å | Mutation | Yes | [10] |
| PDB Sequence |
SGTTNTVAAY
10 NLTWKSTNFK20 TILEWEPKPV30 NQVYTVQIST40 KSGDWKSKCF50 YTTDTECDLT 60 DEIVKDVKQT70 YLARVFSYPA80 GNVESTGSAG90 EPLYENSPEF100 TPYLETNLGQ 110 PTIQSFEQVG120 TKVNVTVEDE130 RTLVRRNNTF140 LSLRDVFGKD150 LIYTLYYWKS 160 SSSGKKTAKT170 NTNEFLIDVD180 KGENYCFSVQ190 AVIPSRTVNR200 KSTDSPVECM 210
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Beta-L-fucose | Ligand Info | |||||
| Structure Description | Crystal Structure of tissue factor-factor VIIa complex | PDB:1J9C | ||||
| Method | X-ray diffraction | Resolution | 2.90 Å | Mutation | No | [11] |
| PDB Sequence |
SGTTNTVAAY
10 NLTWKSTNFK20 TILEWEPKPV30 NQVYTVQIST40 KSGDWKSKCF50 YTTDTECDLT 60 DEIVKDVKQT70 YLARVFSYPA80 GNVESTGSAG90 EPLYENSPEF100 TPYLETNLGQ 110 PTIQSFEQVG120 TKVNVTVEDE130 RTLVRRNNTF140 LSLRDVFGKD150 LIYTLYYWKS 160 SSSGKKTAKT170 NTNEFLIDVD180 KGENYCFSVQ190 AVIPSRTVNR200 KSTDSPVECM 210
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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 | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 8.77E-04 |
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| Closeness centrality | 2.09E-01 | Radiality | 1.37E+01 | Clustering coefficient | 3.21E-01 |
| Neighborhood connectivity | 1.51E+01 | Topological coefficient | 1.76E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Complement and coagulation cascades | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | IL4 Signaling Pathway | |||||
| 2 | TGF_beta_Receptor Signaling Pathway | |||||
| 3 | TWEAK Signaling Pathway | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Angiogenesis | |||||
| 2 | Blood coagulation | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Coagulation | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Extrinsic Pathway of Fibrin Clot Formation | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Complement and Coagulation Cascades | |||||
| 2 | Formation of Fibrin Clot (Clotting Cascade) | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | TETIS study: evaluation of new topical hemostatic agent TT-173 in tooth extraction. Clin Oral Investig. 2016 Jun;20(5):1055-63. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2021. Application Number: 761208. | |||||
| REF 3 | ClinicalTrials.gov (NCT00879606) Anti-TF Antibody (ALT-836) to Treat Septic Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT02012569) Determine the Haemostatic Efficacy of TT-173, Reducing the Bleeding Time in the Donor Site of Skin Grafting. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT01761240) Dose Escalation Study MORAb-066 Targeting TF-expressing Malignancies Including Breast, Pancreatic, Colorectal, NSCLC. U.S. National Institutes of Health. | |||||
| REF 6 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 7 | ImmunoPET of tissue factor expression in triple-negative breast cancer with a radiolabeled antibody Fab fragment. Eur J Nucl Med Mol Imaging. 2015 Jul;42(8):1295-303. | |||||
| REF 8 | Clinical pipeline report, company report or official report of Morphotek. | |||||
| REF 9 | Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors. J Med Chem. 2008 Jun 12;51(11):3077-80. | |||||
| REF 10 | Beating tissue factor at its own game: Design and properties of a soluble tissue factor-independent coagulation factor VIIa. J Biol Chem. 2020 Jan 10;295(2):517-528. | |||||
| REF 11 | Ligand Induced Conformational Transitions of Tissue Factor. Crystal Structure of the Tissue Factor:Factor VIIa Complex. | |||||
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