TTD Target ID: TTDS00301

Target Information
Name	Thymidylate synthase
Type of target	Successful target
Synonyms	HrTS
	Human recombinant thymidylate synthase
	OK/SW-cl.29
	TS
	TSase
Disease	Breast 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)	(+)-Irinotecan		Approved	Colon cancer	[7][8]
	Capecitabine		Approved	Colorectal cancer	[8]
	Floxuridine/5-fluorouracil		Approved	Colorectal cancer	[9]
	Flucytosine		Approved	Fungal infections	[10]
	Fluorouracil		Approved	Cancers	[4][11][2][12]
	Gemcitabine		Approved	Cancers	[13][14]
	Leucovorin/5-fluorouracil		Approved	Colon Cancer	[15][16]
	Pemetrexed		Approved	Pleural mesothelioma	[17]
	Raltitrexed		Approved	Colon and rectum cancers	[18][19]
	Trifluridine		Approved	Viral Infection	[20]
	Capecitabine		Phase III	Breast cancer	[21][22]
	LY231514		Phase III	Non-squamous Non-small Cell Lung Cancer	[23][24]
	Plevitrexed (R)-isomer		Phase II completed	Advanced gastric cancer	[25]
	Plevitrexed		Phase II	Advanced gastric cancer	[25]
BioChemical Class	Transferases transferring one-carbon groups
EC Number	EC 2.1.1.45
Pathway	Metabolic pathways
	One carbon pool by folate
	Pyrimidine metabolism
UniProt ID	O02604
	P04818
	P13100
	P13922
PDB Structure	1CI7; 1F28; 1JU6; 1JUJ; 1YPV; 2ONB; 2RD8; 2RDA.
Sequence	MPVAGSELPRRPLPPAAQERDAEPRPPHGELQYLGQIQHILRCGVRKDDRTGTGTLSVFG MQARYSLRDEFPLLTTKRVFWKGVLEELLWFIKGSTNAKELSSKGVKIWDANGSRDFLDS LGFSTREEGDLGPVYGFQWRHFGAEYRDMESDYSGQGVDQLQRVIDTIKTNPDDRRIIMC AWNPRDLPLMALPPCHALCQFYVVNSELSCQLYQRSGDMGLGVPFNIASYALLTYMIAHI TGLKPGDFIHTLGDAHIYLNHIEPLKIQLQREPRPFPKLRILRKVEKIDDFKAEDFQIEG YNPHPTIKMEMAV
Related US Patent	6,143,776
Target Validation	Click to Find Target Validation Information.
QSAR Model	Click 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]
Ligand	NB1011		[35]
Cross References	3D Structure Related Literature On-Line Medical Dictionary
Ref 1	Thymidylate synthase: a critical target for cancer chemotherapy. Clin Colorectal Cancer. 2002 Feb;1(4):220-9. To Reference
Ref 2	Thymidylate 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 3	The 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 4	The 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 5	Novel molecular targets for antimalarial drug development. Chem Biol Drug Des. 2008 Apr;71(4):287-97. Epub 2008 Feb 22. To Reference
Ref 6	Structure-based discovery and in-parallel optimization of novel competitive inhibitors of thymidylate synthase. Chem Biol. 1999 May;6(5):319-31. To Reference
Ref 7	Predictive 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 8	UGT1A7 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 9	Antisense 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 10	Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9. To Reference
Ref 11	Association 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 12	Acquisition of resistance to anticancer agents by overproduction of target enzymes. Nippon Rinsho. 1997 May;55(5):1030-7. To Reference
Ref 13	Treatment 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 14	Ribonucleotide 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 15	Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Mol Cancer Ther. 2009 Apr 21. [Epub ahead of print] To Reference
Ref 16	Evaluating 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 17	Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40. To Reference
Ref 18	DNA 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 19	Cellular 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 20	Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703. To Reference
Ref 21	Roche. Product Development Pipeline. July 29 2009. To Reference
Ref 22	Roche. Report of Roche. 2009. To Reference
Ref 23	Loss 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 24	J 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 25	Cooperative 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 26	Overington 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 27	J 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 28	Nucleic Acids Res. 2011 January; 39(Database issue): D1035¨CD1041. DrugBank 3.0: a comprehensive resource for ¡®Omics¡¯ research on drugs To Reference
Ref 29	J 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 30	Berman 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 31	Novel molecular targets for antimalarial chemotherapy. Int J Antimicrob Agents. 2007 Jul;30(1):4-10. Epub 2007 Mar 6. To Reference
Ref 32	J 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 33	J 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 34	J 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 35	Kinetic properties of human thymidylate synthase, an anticancer drug target. Biochem Biophys Res Commun. 2003 Jul 25;307(2):297-300. To Reference

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Professor in Department of Pharmacy
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