Target Information
Target General Information | Top | |||||
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Target ID |
T85616
(Former ID: TTDC00075)
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Target Name |
Thioredoxin (TXN)
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Synonyms |
Trx; TRX1; TRDX; Surface-associated sulphydryl protein; Surface associated sulphydryl protein; SASP; ATL-derived factor; ADF
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Gene Name |
TXN
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity. Induces the FOS/JUN AP-1 DNA-binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity. Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions.
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UniProt ID | ||||||
Sequence |
MVKQIESKTAFQEALDAAGDKLVVVDFSATWCGPCKMIKPFFHSLSEKYSNVIFLEVDVD
DCQDVASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEATINELV Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T17CNB |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | PX-12 | Drug Info | Phase 2 | Solid tumour/cancer | [2] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 3 Inhibitor drugs | + | ||||
1 | PX-12 | Drug Info | [1], [3], [4] | |||
2 | Acetate Ion | Drug Info | [5] | |||
3 | Cacodylate Ion | Drug Info | [5] |
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: 2-Mercaptoethanesulfonic acid | Ligand Info | |||||
Structure Description | Crystal structures of thioredoxin with mesna at 1.85A resolution | PDB:4POM | ||||
Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | Yes | [6] |
PDB Sequence |
GTMVKQIESK
8 TAFQKALKAA18 GDKLVVVDFS28 ATWCGPCKMI38 KPFFHSLSEK48 YSNVIFLEVD 58 VDDCQDVASE68 CEVKCMPTFQ78 FFKKGQKVGE88 FSGANKKKLE98 ATINKLV |
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
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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Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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Thioredoxin-like protein 4A (TXNL4A) | 24.752 (25/101) | 4.00E-03 |
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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NOD-like receptor signaling pathway | hsa04621 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy |
Degree | 16 | Degree centrality | 1.72E-03 | Betweenness centrality | 2.18E-03 |
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Closeness centrality | 2.29E-01 | Radiality | 1.40E+01 | Clustering coefficient | 6.67E-02 |
Neighborhood connectivity | 1.64E+01 | Topological coefficient | 7.30E-02 | Eccentricity | 11 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
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NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
1 | IL2 Signaling Pathway | |||||
2 | RANKL Signaling Pathway | |||||
Panther Pathway | [+] 2 Panther Pathways | + | ||||
1 | Hypoxia response via HIF activation | |||||
2 | Oxidative stress response | |||||
Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
1 | Purine Metabolism | |||||
PID Pathway | [+] 3 PID Pathways | + | ||||
1 | p38 MAPK signaling pathway | |||||
2 | Signaling events mediated by PTP1B | |||||
3 | TNF receptor signaling pathway | |||||
Reactome | [+] 4 Reactome Pathways | + | ||||
1 | Oxidative Stress Induced Senescence | |||||
2 | Detoxification of Reactive Oxygen Species | |||||
3 | TP53 Regulates Metabolic Genes | |||||
4 | The NLRP3 inflammasome | |||||
WikiPathways | [+] 8 WikiPathways | + | ||||
1 | NRF2 pathway | |||||
2 | Nuclear Receptors Meta-Pathway | |||||
3 | Detoxification of Reactive Oxygen Species | |||||
4 | Human Complement System | |||||
5 | Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways | |||||
6 | TNF alpha Signaling Pathway | |||||
7 | Metabolism of nucleotides | |||||
8 | Selenium Micronutrient Network |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | 2-[(1-methylpropyl)dithio]-1H-imidazole inhibits tubulin polymerization through cysteine oxidation. Mol Cancer Ther. 2008 Jan;7(1):143-51. | |||||
REF 2 | The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma. J Lab Clin Med. 2006 Feb;147(2):83-90. | |||||
REF 3 | Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. | |||||
REF 4 | A Phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors. Clin Cancer Res. 2007 Apr 1;13(7):2109-14. | |||||
REF 5 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 6 | BNP7787 Forms Novel Covalent |
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