Therapeutic Targets Database
BIDD Pharmainformatics Databases
 
   
 

 

TTD Target ID: TTDS00301

Target Information
NameThymidylate synthase    
Type of targetSuccessful target    
SynonymsHrTS    
Human recombinant thymidylate synthase    
OK/SW-cl.29    
TS    
TSase    
DiseaseBreast cancer    [1]
Colorectal cancer    [2][1]
Fungal diseases    [3]
Gastric cancer    [1]
Hepatocellular carcinoma    [4]
Malaria    [5]
Ovarian cancer    [1]
Pancreatic cancer    [1]
Proliferative diseases    [6]
Drug(s)(+)-IrinotecanApprovedColon cancer[7][8]
CapecitabineApprovedColorectal cancer [8]
Floxuridine/5-fluorouracilApprovedColorectal cancer[9]
FlucytosineApprovedFungal infections[10]
FluorouracilApprovedCancers[4][11][2][12]
GemcitabineApprovedCancers[13][14]
Leucovorin/5-fluorouracilApprovedColon Cancer[15][16]
PemetrexedApprovedPleural mesothelioma [17]
RaltitrexedApprovedColon and rectum cancers[18][19]
TrifluridineApprovedViral Infection [20]
CapecitabinePhase IIIBreast cancer[21][22]
LY231514Phase IIINon-squamous Non-small Cell Lung Cancer[23][24]
Plevitrexed (R)-isomerPhase II completedAdvanced gastric cancer[25]
PlevitrexedPhase IIAdvanced gastric cancer[25]
BioChemical ClassTransferases transferring one-carbon groups    
EC NumberEC 2.1.1.45
PathwayMetabolic pathways
One carbon pool by folate
Pyrimidine metabolism
UniProt IDO02604
P04818
P13100
P13922
PDB Structure1CI7; 1F28; 1JU6; 1JUJ; 1YPV; 2ONB; 2RD8; 2RDA.    
SequenceMPVAGSELPRRPLPPAAQERDAEPRPPHGELQYLGQIQHILRCGVRKDDRTGTGTLSVFG MQARYSLRDEFPLLTTKRVFWKGVLEELLWFIKGSTNAKELSSKGVKIWDANGSRDFLDS LGFSTREEGDLGPVYGFQWRHFGAEYRDMESDYSGQGVDQLQRVIDTIKTNPDDRRIIMC AWNPRDLPLMALPPCHALCQFYVVNSELSCQLYQRSGDMGLGVPFNIASYALLTYMIAHI TGLKPGDFIHTLGDAHIYLNHIEPLKIQLQREPRPFPKLRILRKVEKIDDFKAEDFQIEG YNPHPTIKMEMAV
Related US Patent6,143,776
Target ValidationClick to Find Target Validation Information.    
QSAR ModelClick to Find Target QSAR Model.    
Inhibitor (+)-Irinotecan[7][8]
(6s)-5,6,7,8-Tetrahydrofolate[26]
1,3-propanediphosphonic acid[27]
1,4-Dithiothreitol[26]
10-Propargyl-5,8-Dideazafolic Acid[26]
2'-5'dideoxyuridine[28]
2'-Deoxycytidine-5'-Monophosphate[26]
2'-Deoxyguanosine-5'-Monophosphate[26]
2'-Deoxyuridine[26]
2'-deoxyuridylic acid[26]
2-bromophenol[28]
3-Amino-5,6-dihydro-2H-benzo[f]quinazolin-1-one[29]
3-DIPHENOL-6-NITRO-3H-BENZO[DE]ISOCHROMEN-1-ONE[30]
3-Methyl-2H-benzo[f]quinazolin-1-one[29]
4-CHLORO-3',3''-DIBROMOPHENOL-1,8-NAPHTHALEIN[28]
5,10-Methylene-6-Hydrofolic Acid[26]
5-Fluoro-2'-Deoxyuridine-5'-Monophosphate[26]
5-Fluoroorotate[5]
5-Fluoroorotate[31]
5-Fluorouracil[4][11][2][12]
6-ETHYL-5-PHENYLPYRIMIDINE-2,4-DIAMINE[30]
Beta-Mercaptoethanol[26]
CB-3717[32]
Capecitabine[8]
Capecitabine[21][22]
Floxuridine/5-fluorouracil[9]
Flucytosine[10]
Fluorouracil[4][11][2][12]
GW1843[23]
Gemcitabine[13][14]
LY231514[23][24]
LY341770[26]
Leucovorin/5-fluorouracil[15][16]
Ly231514 Tetra Glu[26]
N,O-Didansyl-L-Tyrosine[26]
N-Carboxymethionine[26]
N-[Tosyl-D-Prolinyl]Amino-Ethanethiol[26]
PDDF[33]
PREMETREXED[34]
Pemetrexed[17]
Plevitrexed[25]
Plevitrexed (R)-isomer[25]
Raltitrexed[18][19]
S,S- (2-Hydroxyethyl)Thiocysteine[26]
S-Oxymethionine[30]
Sp-722[26]
Sp-876[26]
Thymidine-5'-Phosphate[26]
Tosyl-D-Proline[26]
Trifluridine[20]
Uridine-5'-Monophosphate[26]
ZD1604[12]
ZD9331[1]
LigandNB1011[35]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Thymidylate synthase: a critical target for cancer chemotherapy. Clin Colorectal Cancer. 2002 Feb;1(4):220-9. To Reference
Ref 2Thymidylate synthase expression in patients with colorectal carcinoma using a polyclonal thymidylate synthase antibody in comparison to the TS 106 monoclonal antibody. J Histochem Cytochem. 2000 Jun;48(6):755-60. To Reference
Ref 3The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design. J Mol Biol. 2000 Mar 31;297(3):645-57. To Reference
Ref 4The efficacy of the combination therapy of 5-fluorouracil, cisplatin and leucovorin for hepatocellular carcinoma and its predictable factors. Cancer Chemother Pharmacol. 2004 Apr;53(4):296-304. Epub 2003 Dec 20. To Reference
Ref 5Novel molecular targets for antimalarial drug development. Chem Biol Drug Des. 2008 Apr;71(4):287-97. Epub 2008 Feb 22. To Reference
Ref 6Structure-based discovery and in-parallel optimization of novel competitive inhibitors of thymidylate synthase. Chem Biol. 1999 May;6(5):319-31. To Reference
Ref 7Predictive and prognostic markers for the outcome of chemotherapy in advanced colorectal cancer, a retrospective analysis of the phase III randomised CAIRO study. Eur J Cancer. 2009 Jul;45(11):1999-2006. Epub 2009 May 18. To Reference
Ref 8UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res. 2005 Feb 1;11(3):1226-36. To Reference
Ref 9Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells. Br J Pharmacol. 1999 Aug;127(8):1777-86. To Reference
Ref 10Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9. To Reference
Ref 11Association of gastric and intestinal phenotypic marker expression of gastric carcinomas with tumor thymidylate synthase expression and response to postoperative chemotherapy with 5-fluorouracil. J Cancer Res Clin Oncol. 2003 Dec;129(12):683-90. Epub 2003 Oct 24. To Reference
Ref 12Acquisition of resistance to anticancer agents by overproduction of target enzymes. Nippon Rinsho. 1997 May;55(5):1030-7. To Reference
Ref 13Treatment of advanced pancreatic cancer: from gemcitabine single agent to combinations and targeted therapy. Cancer Treat Rev. 2009 Jun;35(4):335-9. Epub 2009 Jan 7. To Reference
Ref 14Ribonucleotide reductase M1 (RRM1) 2464G>A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines. Pharmacogenet Genomics. 2006 Jun;16(6):429-38. To Reference
Ref 15Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Mol Cancer Ther. 2009 Apr 21. [Epub ahead of print] To Reference
Ref 16Evaluating the drug-target relationship between thymidylate synthase expression and tumor response to 5-fluorouracil. Is it time to move forward? Cancer Biol Ther. 2008 Jul;7(7):986-94. Epub 2008 Apr 21. To Reference
Ref 17Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40. To Reference
Ref 18DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96. Epub 2008 Aug 19. To Reference
Ref 19Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol. 1999 Apr;26(2 Suppl 6):48-54. To Reference
Ref 20Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703. To Reference
Ref 21Roche. Product Development Pipeline. July 29 2009. To Reference
Ref 22Roche. Report of Roche. 2009. To Reference
Ref 23Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. Int J Cancer. 2003 Feb 20;103(5):587-99. To Reference
Ref 24J Med Chem. 2001 Jun 7;44(12):1993-2003.Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. To Reference
Ref 25Cooperative inhibition of human thymidylate synthase by mixtures of active site binding and allosteric inhibitors. Biochemistry. 2007 Mar 13;46(10):2823-30. Epub 2007 Feb 13. To Reference
Ref 26Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 27J Med Chem. 2010 Sep 23;53(18):6539-49.Novel approaches for targeting thymidylate synthase to overcome the resistance and toxicity of anticancer drugs. To Reference
Ref 28Nucleic Acids Res. 2011 January; 39(Database issue): D1035¨CD1041. DrugBank 3.0: a comprehensive resource for ¡®Omics¡¯ research on drugs To Reference
Ref 29J Med Chem. 1993 Oct 29;36(22):3464-71.Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some sulfonamidobenzoylglutamate and related derivatives. To Reference
Ref 30Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. To Reference
Ref 31Novel molecular targets for antimalarial chemotherapy. Int J Antimicrob Agents. 2007 Jul;30(1):4-10. Epub 2007 Mar 6. To Reference
Ref 32J Med Chem. 2009 Aug 13;52(15):4892-902.Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents. To Reference
Ref 33J Med Chem. 2005 Nov 17;48(23):7215-22.Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents. To Reference
Ref 34J Med Chem. 2006 Feb 9;49(3):1055-65.Dual inhibitors of thymidylate synthase and dihydrofolate reductase as antitumor agents: design, synthesis, and biological evaluation of classical and nonclassical pyrrolo[2,3-d]pyrimidine antifolates(1). To Reference
Ref 35Kinetic properties of human thymidylate synthase, an anticancer drug target. Biochem Biophys Res Commun. 2003 Jul 25;307(2):297-300. To Reference



 

Welcome to sign our Guestbook.

If you find any error in data or bug in web service, please kindly report it to Dr. Zhu.


Dr. Chen Yuzong
Deputy Director of Center for Computational Science and Engineering
Professor in Department of Pharmacy
National University of Singapore, Singapore


All rights reserved.

 
   
           
 
Computer-aided Drug Design
About BIDD | Databases | Software | Teaching | Research |  Links

Department of Computational Science | National University of Singapore | Blk S17, 3 Science Drive 2, Singapore 117543