Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTP3QRF)

• DTT Name: Thymidine kinase 1 (TK1)
• Synonyms: Thymidine kinase, cytosolic
• Gene Name: TK1
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: KITH_HUMAN
• TTD ID: T30081
• EC Number: EC 2.7.1.21
• Sequence:
  MSCINLPTVLPGSPSKTRGQIQVILGPMFSGKSTELMRRVRRFQIAQYKCLVIKYAKDTR
  YSSSFCTHDRNTMEALPACLLRDVAQEALGVAVIGIDEGQFFPDIVEFCEAMANAGKTVI
  VAALDGTFQRKPFGAILNLVPLAESVVKLTAVCMECFREAAYTKRLGTEKEVEVIGGADK
  YHSVCRLCYFKKASGQPAGPDNKENCPVPGKPGEAVAARKLFAPQQILQCSPAN
• 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
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Pyrimidine salvage (R-HSA-73614)
  G1/S-Specific Transcription (R-HSA-69205)
• BioCyc Pathway: MetaCyc:HS09657-MON

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DEOXYCYTIDINE	DMYE5LJ	Acute myeloid leukaemia	2A60	Approved	[2]
Penciclovir	DMOUMDV	Herpes simplex labialis	1F00.01	Approved	[1]

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TK-DLI	DM26I8H	Graft-versus-host disease	4B24	Preregistration	[3]
FV-100	DMZARP1	Varicella zoster virus infection	1E91	Phase 3	[4]
Radiosensitizer gene therapy	DMN1ZEU	Pancreatic cancer	2C10	Phase 3	[5]
RP101	DMNIYSZ	Infectious disease	1A00-CA43.1	Phase 2/3	[6]
HQK-1004	DM3WX0K	Solid tumour/cancer	2A00-2F9Z	Phase 2	[7]
Ad-OC-hsvTK/valacyclovir	DM9GLHO	Prostate cancer	2C82.0	Phase 1	[8]
Rilapladib	DMB9861	Arteriosclerosis	BD40	Phase 1	[9]
Thymidine kinase-expressing adenovirus and ganciclovir suicide gene therapy	DMO8SGD	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Sitimagene ceradenovec	DM0T2QV	Brain cancer	2A00	Discontinued in Phase 3	[11]

28 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(South)-Methanocarba-Thymidine	DMT3S72	Discovery agent	N.A.	Investigative	[1]
1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine	DMU3VWA	Discovery agent	N.A.	Investigative	[12]
1-[2-(2-triphenylmethoxyethoxy)ethyl]thymine	DMDZA83	Discovery agent	N.A.	Investigative	[12]
1-[5-(triphenylmethoxy)pentyl]thymine	DMFHBJM	Discovery agent	N.A.	Investigative	[12]
1-[6-(triphenylmethoxy)hexyl]thymine	DM5NVHO	Discovery agent	N.A.	Investigative	[12]
1-[7-(triphenylmethoxy)heptyl]thymine	DMQ05F2	Discovery agent	N.A.	Investigative	[12]
2'-deoxythymidine triphosphate	DM9OEJT	Discovery agent	N.A.	Investigative	[1]
2'-Deoxyuridine	DM1HMWA	Discovery agent	N.A.	Investigative	[2]
2-phenylamino-9-(4-hydroxy-butyl)-6-oxopurine	DMW0M14	Discovery agent	N.A.	Investigative	[13]
3'-(1,2,3-Triazol-1-yl)-3'-deoxy-beta-D-thymidine	DM5UL3F	Discovery agent	N.A.	Investigative	[14]
3-(2-propyn-1-yl)thymidine	DM2IYAP	Discovery agent	N.A.	Investigative	[15]
5-Bromothienyldeoxyuridine	DMZ8X3H	Discovery agent	N.A.	Investigative	[1]
5-Iodo-2'-Deoxyuridine-5'-Monophosphate	DMZACXG	Discovery agent	N.A.	Investigative	[1]
5-propyl-2'-deoxyuridine	DM9IHV6	Discovery agent	N.A.	Investigative	[13]
6-(Dihydroxy-Isobutyl)-Thymine	DMQPTL5	Discovery agent	N.A.	Investigative	[1]
6-Hydroxypropylthymine	DMVRFU5	Discovery agent	N.A.	Investigative	[1]
9-(4-Hydroxybutyl)-N2-Phenylguanine	DMLKJD9	Discovery agent	N.A.	Investigative	[1]
9-Hydroxypropyladenine, R-Isomer	DMB9FCK	Discovery agent	N.A.	Investigative	[1]
9-Hydroxypropyladenine, S-Isomer	DM8QJUH	Discovery agent	N.A.	Investigative	[1]
BVDU-MP	DMI1H3Y	Discovery agent	N.A.	Investigative	[16]
Deoxythymidine	DMR90HY	Discovery agent	N.A.	Investigative	[1]
Edoxudine	DMC7DYX	Discovery agent	N.A.	Investigative	[13]
ITdU	DMA8F4N	Discovery agent	N.A.	Investigative	[9]
L-5-(bromovinyl)deoxyuridine	DMHL901	Discovery agent	N.A.	Investigative	[13]
L-5-iodo-2'-deoxyuridine	DM3Q0JL	Discovery agent	N.A.	Investigative	[13]
N2-(3-trifluoromethylphenyl)guanine	DMGJEH9	Discovery agent	N.A.	Investigative	[13]
P1-(5'-Adenosyl)P5-(5'-Thymidyl)Pentaphosphate	DMM4VWD	Discovery agent	N.A.	Investigative	[6]
Thymidine-5'-Phosphate	DMKM6NQ	Discovery agent	N.A.	Investigative	[1]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	1.14E-03	0.26	0.75
Neuroectodermal tumour	2C82	Nervous tissue	7.79E-76	0.42	1.38

References

• [1] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [2] 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.
• [3] Company report (Takara Bio)
• [4] 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.
• [5] Pronounced antitumor effects and tumor radiosensitization of double suicide gene therapy. Clin Cancer Res. 1997 Nov;3(11):2081-8.
• [6] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [7] 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.
• [8] 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.
• [9] Trichomonas vaginalis thymidine kinase: purification, characterization and search for inhibitors. Biochem J. 1998 Aug 15;334 ( Pt 1):15-22.
• [10] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [11] Sitimagene ceradenovec: a gene-based drug for the treatment of operable high-grade glioma. Future Oncol. 2010 Nov;6(11):1691-710.
• [12] N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors. J Med Chem. 2006 Dec 28;49(26):7766-73.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Crystal structure of varicella zoster virus thymidine kinase. J Biol Chem. 2003 Jul 4;278(27):24680-7.