Target Information
| Target General Information | Top | |||||
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| Target ID |
T30081
(Former ID: TTDR00500)
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| Target Name |
Thymidine kinase 1 (TK1)
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| Synonyms |
Thymidine kinase, cytosolic
Click to Show/Hide
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| Gene Name |
TK1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Human immunodeficiency virus disease [ICD-11: 1C60-1C62] | |||||
| Function |
cytosol, identical protein binding, thymidine kinase activity, zinc ion binding, DNA metabolic process, nucleobase-containing compound metabolic process, protein homotetramerization, pyrimidine nucleoside salvage, thymidine metabolic process
Click to Show/Hide
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.1.21
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| Sequence |
MSCINLPTVLPGSPSKTRGQIQVILGPMFSGKSTELMRRVRRFQIAQYKCLVIKYAKDTR
YSSSFCTHDRNTMEALPACLLRDVAQEALGVAVIGIDEGQFFPDIVEFCEAMANAGKTVI VAALDGTFQRKPFGAILNLVPLAESVVKLTAVCMECFREAAYTKRLGTEKEVEVIGGADK YHSVCRLCYFKKASGQPAGPDNKENCPVPGKPGEAVAARKLFAPQQILQCSPAN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A05675 ; BADD_A06627 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | DEOXYCYTIDINE | Drug Info | Approved | Acute myeloid leukaemia | [2], [3] | |
| 2 | Penciclovir | Drug Info | Approved | Human immunodeficiency virus infection | [2], [4] | |
| Clinical Trial Drug(s) | [+] 8 Clinical Trial Drugs | + | ||||
| 1 | TK-DLI | Drug Info | Preregistration | Graft-versus-host disease | [5] | |
| 2 | FV-100 | Drug Info | Phase 3 | Varicella zoster virus infection | [6] | |
| 3 | Radiosensitizer gene therapy | Drug Info | Phase 3 | Pancreatic cancer | [7] | |
| 4 | RP101 | Drug Info | Phase 2/3 | Pancreatic cancer | [8] | |
| 5 | HQK-1004 | Drug Info | Phase 2 | Solid tumour/cancer | [9] | |
| 6 | Ad-OC-hsvTK/valacyclovir | Drug Info | Phase 1 | Prostate cancer | [10] | |
| 7 | Rilapladib | Drug Info | Phase 1 | Cardiovascular disease | [11] | |
| 8 | Thymidine kinase-expressing adenovirus and ganciclovir suicide gene therapy | Drug Info | Phase 1 | Solid tumour/cancer | [12] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Sitimagene ceradenovec | Drug Info | Discontinued in Phase 3 | Brain cancer | [13] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 35 Inhibitor drugs | + | ||||
| 1 | DEOXYCYTIDINE | Drug Info | [14] | |||
| 2 | Penciclovir | Drug Info | [1] | |||
| 3 | FV-100 | Drug Info | [16] | |||
| 4 | Radiosensitizer gene therapy | Drug Info | [17] | |||
| 5 | RP101 | Drug Info | [18] | |||
| 6 | Ad-OC-hsvTK/valacyclovir | Drug Info | [20] | |||
| 7 | Rilapladib | Drug Info | [21] | |||
| 8 | (South)-Methanocarba-Thymidine | Drug Info | [1] | |||
| 9 | 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine | Drug Info | [24] | |||
| 10 | 1-[2-(2-triphenylmethoxyethoxy)ethyl]thymine | Drug Info | [24] | |||
| 11 | 1-[5-(triphenylmethoxy)pentyl]thymine | Drug Info | [24] | |||
| 12 | 1-[6-(triphenylmethoxy)hexyl]thymine | Drug Info | [24] | |||
| 13 | 1-[7-(triphenylmethoxy)heptyl]thymine | Drug Info | [24] | |||
| 14 | 2'-deoxythymidine triphosphate | Drug Info | [1] | |||
| 15 | 2'-Deoxyuridine | Drug Info | [14] | |||
| 16 | 2-phenylamino-9-(4-hydroxy-butyl)-6-oxopurine | Drug Info | [25] | |||
| 17 | 3'-(1,2,3-Triazol-1-yl)-3'-deoxy-beta-D-thymidine | Drug Info | [26] | |||
| 18 | 3-(2-propyn-1-yl)thymidine | Drug Info | [27] | |||
| 19 | 5-Bromothienyldeoxyuridine | Drug Info | [1] | |||
| 20 | 5-Iodo-2'-Deoxyuridine-5'-Monophosphate | Drug Info | [1] | |||
| 21 | 5-propyl-2'-deoxyuridine | Drug Info | [25] | |||
| 22 | 6-(Dihydroxy-Isobutyl)-Thymine | Drug Info | [1] | |||
| 23 | 6-Hydroxypropylthymine | Drug Info | [1] | |||
| 24 | 9-(4-Hydroxybutyl)-N2-Phenylguanine | Drug Info | [1] | |||
| 25 | 9-Hydroxypropyladenine, R-Isomer | Drug Info | [1] | |||
| 26 | 9-Hydroxypropyladenine, S-Isomer | Drug Info | [1] | |||
| 27 | BVDU-MP | Drug Info | [28] | |||
| 28 | Deoxythymidine | Drug Info | [1] | |||
| 29 | Edoxudine | Drug Info | [25] | |||
| 30 | ITdU | Drug Info | [21] | |||
| 31 | L-5-(bromovinyl)deoxyuridine | Drug Info | [25] | |||
| 32 | L-5-iodo-2'-deoxyuridine | Drug Info | [25] | |||
| 33 | N2-(3-trifluoromethylphenyl)guanine | Drug Info | [25] | |||
| 34 | P1-(5'-Adenosyl)P5-(5'-Thymidyl)Pentaphosphate | Drug Info | [18] | |||
| 35 | Thymidine-5'-Phosphate | Drug Info | [1] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | TK-DLI | Drug Info | [15] | |||
| 2 | HQK-1004 | Drug Info | [19] | |||
| 3 | Thymidine kinase-expressing adenovirus and ganciclovir suicide gene therapy | Drug Info | [22] | |||
| 4 | Sitimagene ceradenovec | Drug Info | [23] | |||
| 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'-deoxythymidine triphosphate | Ligand Info | |||||
| Structure Description | Structure of a type II thymidine kinase with bound dTTP | PDB:1W4R | ||||
| Method | X-ray diffraction | Resolution | 1.83 Å | Mutation | No | [29] |
| PDB Sequence |
RGQIQVILGP
27 MFSGKSTELM37 RRVRRFQIAQ47 YKCLVIKYAK57 DTRYSSSFCT67 HDRNTMEALP 77 ACLLRDVAQE87 ALGVAVIGID97 EGQFFPDIVE107 FCEAMANAGK117 TVIVAALDGT 127 FQRKPFGAIL137 NLVPLAESVV147 KLTAVCMECF157 REAAYTKRLG167 TEKEVEVIGG 177 ADKYHSVCRL187 CYFK
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PRO27
3.803
MET28
3.500
PHE29
2.911
SER30
3.400
GLY31
3.002
LYS32
2.538
SER33
3.195
THR34
4.745
ASP58
2.694
ARG60
3.246
SER63
4.440
ASP97
4.680
GLU98
3.440
GLN100
4.037
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: P(1)-(Adenosine-5')-P(5)-(thymidine-5')-pentaphosphate | Ligand Info | |||||
| Structure Description | human Thymidine Kinase 1 in complex with TP4A | PDB:2ORV | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [30] |
| PDB Sequence |
RGQIQVILGP
27 MFSGKSTELM37 RRVRRFQIAQ47 YKCLVIKYAK57 DTRYMEALPA78 CLLRDVAQEA 88 LGVAVIGIDE98 GQFFPDIVEF108 CEAMANAGKT118 VIVAALDGTF128 QRKPFGAILN 138 LVPLAESVVK148 LTAVCMECFR158 EAAYTKRLGT168 EKEVEVIGGA178 DKYHSVCRLC 188 YFK
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PRO27
4.111
MET28
3.378
PHE29
3.280
SER30
3.289
GLY31
2.921
LYS32
2.695
SER33
2.894
THR34
4.529
ASP58
2.916
ARG60
3.341
ASP97
2.930
GLU98
3.317
GLN100
3.276
PHE101
3.119
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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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| Pyrimidine metabolism | hsa00240 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| Drug metabolism - other enzymes | hsa00983 | Affiliated Target |
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| Class: Metabolism => Xenobiotics biodegradation and metabolism | Pathway Hierarchy | ||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 1.48E-03 |
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| Closeness centrality | 2.06E-01 | Radiality | 1.36E+01 | Clustering coefficient | 3.81E-01 |
| Neighborhood connectivity | 1.70E+01 | Topological coefficient | 1.89E-01 | 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 Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating Transcription Factors | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000912) | |||||
| REF 4 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023073) | |||||
| REF 6 | ClinicalTrials.gov (NCT02412917) A Comparative Study of FV-100 vs. Valacyclovir for the Prevention of Post-Herpetic Neuralgia. U.S. National Institutes of Health. | |||||
| REF 7 | Clinical pipeline report, company report or official report of Advantagene. | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020300) | |||||
| REF 9 | ClinicalTrials.gov (NCT00992732) Study of HQK-1004 and Valganciclovir to Treat Epstein-Barr Virus (EBV) - Positive Lymphoid Malignancies or Lymphoproliferative Disorders. U.S. National Institutes of Health. | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007778) | |||||
| REF 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018454) | |||||
| REF 12 | ClinicalTrials.gov (NCT00964756) A Study of an Infectivity Enhanced Suicide Gene Expressing Adenovirus for Ovarian Cancer in Patients With Recurrent Ovarian and Other Selected Gynecologic Cancers. U.S. National Institutes of Health. | |||||
| REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015264) | |||||
| REF 14 | Species- or isozyme-specific enzyme inhibitors. 5. Differential effects of thymidine substituents on affinity for rat thymidine kinase isozymes. J Med Chem. 1982 Jun;25(6):644-9. | |||||
| REF 15 | Company report (Takara Bio) | |||||
| REF 16 | Specific recognition of the bicyclic pyrimidine nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded thymidine kinase. Mol Pharmacol. 2002 Feb;61(2):249-54. | |||||
| REF 17 | Pronounced antitumor effects and tumor radiosensitization of double suicide gene therapy. Clin Cancer Res. 1997 Nov;3(11):2081-8. | |||||
| REF 18 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41. | |||||
| REF 19 | Induction of the Epstein-Barr virus thymidine kinase gene with concomitant nucleoside antivirals as a therapeutic strategy for Epstein-Barr virus-associated malignancies. Curr Opin Oncol. 2001 Sep;13(5):360-7. | |||||
| REF 20 | Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. Hum Gene Ther. 2003 Feb 10;14(3):227-41. | |||||
| REF 21 | Trichomonas vaginalis thymidine kinase: purification, characterization and search for inhibitors. Biochem J. 1998 Aug 15;334 ( Pt 1):15-22. | |||||
| REF 22 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 23 | Sitimagene ceradenovec: a gene-based drug for the treatment of operable high-grade glioma. Future Oncol. 2010 Nov;6(11):1691-710. | |||||
| REF 24 | N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors. J Med Chem. 2006 Dec 28;49(26):7766-73. | |||||
| REF 25 | Sensitivity of monkey B virus (Cercopithecine herpesvirus 1) to antiviral drugs: role of thymidine kinase in antiviral activities of substrate anal... Antimicrob Agents Chemother. 2007 Jun;51(6):2028-34. | |||||
| REF 26 | 3'-[4-Aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues as potent and selective inhibitors of human mitochondrial thymidine kinase. J Med Chem. 2010 Apr 8;53(7):2902-12. | |||||
| REF 27 | Synthesis, in vitro, and in silico evaluation of organometallic technetium and rhenium thymidine complexes with retained substrate activity toward ... J Med Chem. 2008 Nov 13;51(21):6689-98. | |||||
| REF 28 | Crystal structure of varicella zoster virus thymidine kinase. J Biol Chem. 2003 Jul 4;278(27):24680-7. | |||||
| REF 29 | Structure of a type II thymidine kinase with bound dTTP. FEBS Lett. 2005 Feb 28;579(6):1376-82. | |||||
| REF 30 | Binding of ATP to TK1-like enzymes is associated with a conformational change in the quaternary structure. J Mol Biol. 2007 May 25;369(1):129-41. | |||||
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