Target Information

Target General Infomation
Target ID
T52227
Former ID
TTDS00301
Target Name
Thymidylate synthase
Gene Name
TMP1
Synonyms
HrTS; Human recombinant thymidylate synthase; OK/SW-cl.29; TS; TSase; TMP1
Target Type
Successful
Disease Advanced gastric cancer [ICD9: 151; ICD10: C16]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Biliary cancer [ICD10: C22, C24]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Colon cancer [ICD9: 153, 154; ICD10: C50]
Colorectal cancer [ICD9: 153, 154; ICD10: C18-C21]
Colon cancer; Rectal cancer [ICD9: 153, 154; ICD10: C50]
Endocarditis [ICD9: 421; ICD10: I33]
Keratosis [ICD10: L57.0]
Malignant pleural mesothelioma [ICD9: 163; ICD10: C45]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Viral infections [ICD9: 054.0, 054.1, 054.2, 054.3, 075, 771.2, 052, 053; ICD10: B01, B02, A60, B00, B27, G05.1, P35.2]
Function
Contributes to thede novo mitochondrial thymidylate biosynthesis pathway.
BioChemical Class
Methyltransferase superfamily
Target Validation
T52227
UniProt ID
P12461
EC Number
EC 2.1.1.45
Sequence
MTVSPNTAEQAYLDLCKRIIDEGEHRPDRTGTGTKSLFAPPQLRFDLSNDTFPLLTTKKV
FSKGIIHELLWFVAGSTDAKILSEKGVKIWEGNGSREFLDKLGLTHRREGDLGPVYGFQW
RHFGAEYKDCDSDYTGQGFDQLQDVIKKLKTNPYDRRIIMSAWNPPDFAKMALPPCHVFC
QFYVNFPTSSPDPNNPKQAKTAKPKLSCLLYQRSCDMGLGVPFNIASYALLTKMIAHVVD
MDCGEFIHTLGDAHVYLDHIDALKEQFERIPKQFPKLVIKEERKNEIKSIDDFKFEDFEI
VGYEPYPPIKMKMSV
Drugs and Mode of Action
Drug(s) Capecitabine Drug Info Approved Colorectal cancer [1], [2]
Floxuridine/5-fluorouracil Drug Info Approved Colorectal cancer [1]
Flucytosine Drug Info Approved Endocarditis [3], [4]
Fluorouracil Drug Info Approved Cancer [1]
Leucovorin/5-fluorouracil Drug Info Approved Colon cancer [1]
Pemetrexed Drug Info Approved Malignant pleural mesothelioma [5], [6], [7], [8], [4]
Raltitrexed Drug Info Approved Colon cancer; Rectal cancer [1], [9]
Trifluridine Drug Info Approved Viral infections [10], [11]
Capecitabine Drug Info Phase 3 Breast cancer [1], [2]
Nolatrexed Drug Info Phase 3 Solid tumours [12]
Plevitrexed Drug Info Phase 2 Advanced gastric cancer [13], [14]
Plevitrexed (R)-isomer Drug Info Phase 2 Advanced gastric cancer [13]
PREMETREXED Drug Info Phase 2 Discovery agent [15]
UFT/leucovorin calcium Drug Info Phase 2 Colorectal cancer [16]
NB1011 Drug Info Phase 1/2 Breast cancer [17]
DFP-11207 Drug Info Phase 1 Solid tumours [18]
GW1843 Drug Info Phase 1 Biliary cancer [19]
EMITEFUR Drug Info Discontinued in Preregistration Solid tumours [20]
GALOCITABINE Drug Info Discontinued in Phase 3 Solid tumours [21]
FO-152 Drug Info Discontinued in Phase 2 Cancer [22]
TT-62 Drug Info Discontinued in Phase 2 Viral infections [23]
AG-331 Drug Info Discontinued in Phase 1 Solid tumours [24]
DMPDDF Drug Info Terminated Cancer [25]
Fosfluridine tidoxil Drug Info Terminated Keratosis [26]
Inhibitor (6s)-5,6,7,8-Tetrahydrofolate Drug Info [27]
1,3-propanediphosphonic acid Drug Info [28]
1,4-Dithiothreitol Drug Info [27]
10-Propargyl-5,8-Dideazafolic Acid Drug Info [27]
2'-5'dideoxyuridine Drug Info [29]
2'-Deoxycytidine-5'-Monophosphate Drug Info [27]
2'-Deoxyguanosine-5'-Monophosphate Drug Info [27]
2'-Deoxyuridine Drug Info [27]
2'-deoxyuridylic acid Drug Info [27]
2-bromophenol Drug Info [29]
3-Amino-5,6-dihydro-2H-benzo[f]quinazolin-1-one Drug Info [30]
3-DIPHENOL-6-NITRO-3H-BENZO[DE]ISOCHROMEN-1-ONE Drug Info [31]
3-Methyl-2H-benzo[f]quinazolin-1-one Drug Info [30]
4-CHLORO-3',3''-DIBROMOPHENOL-1,8-NAPHTHALEIN Drug Info [29]
5,10-Methylene-6-Hydrofolic Acid Drug Info [27]
5-Fluoro-2'-Deoxyuridine-5'-Monophosphate Drug Info [27]
5-Fluorouracil Drug Info [32], [33], [34], [35]
6-ETHYL-5-PHENYLPYRIMIDINE-2,4-DIAMINE Drug Info [31]
AG-331 Drug Info [36]
Beta-Mercaptoethanol Drug Info [27]
Capecitabine Drug Info [37]
CB-3717 Drug Info [38]
DFP-11207 Drug Info [39]
DMPDDF Drug Info [40]
EMITEFUR Drug Info [41]
Floxuridine/5-fluorouracil Drug Info [42]
Flucytosine Drug Info [3]
Fluorouracil Drug Info [32], [33], [34], [35]
Fosfluridine tidoxil Drug Info [43]
GALOCITABINE Drug Info [44]
GW1843 Drug Info [45]
Leucovorin/5-fluorouracil Drug Info [46], [47]
Ly231514 Tetra Glu Drug Info [27]
LY341770 Drug Info [27]
N,O-Didansyl-L-Tyrosine Drug Info [27]
N-Carboxymethionine Drug Info [27]
N-[Tosyl-D-Prolinyl]Amino-Ethanethiol Drug Info [27]
Nolatrexed Drug Info [48]
PDDF Drug Info [49]
Pemetrexed Drug Info [50]
Plevitrexed Drug Info [51]
Plevitrexed (R)-isomer Drug Info [51]
PREMETREXED Drug Info [52]
Raltitrexed Drug Info [53], [54]
S,S-(2-Hydroxyethyl)Thiocysteine Drug Info [27]
S-Oxymethionine Drug Info [31]
Sp-722 Drug Info [27]
Sp-876 Drug Info [27]
Thymidine-5'-Phosphate Drug Info [27]
Tosyl-D-Proline Drug Info [27]
Trifluridine Drug Info [55]
TT-62 Drug Info [56]
Uridine-5'-Monophosphate Drug Info [27]
ZD1604 Drug Info [35]
Modulator FO-152 Drug Info [57]
OVI-117 Drug Info [57]
UFT/leucovorin calcium Drug Info [58]
Binder NB1011 Drug Info [59]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
DRM DRM Info
Pathways
BioCyc Pathway Pyrimidine deoxyribonucleotides biosynthesis from CTP
Pyrimidine deoxyribonucleotides de novo biosynthesis
Superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis
Superpathway of pyrimidine deoxyribonucleoside salvage
DTMP de novo biosynthesis (mitochondrial)
Pyrimidine deoxyribonucleosides salvage
KEGG Pathway Pyrimidine metabolism
One carbon pool by folate
Metabolic pathways
PANTHER Pathway De novo pyrimidine deoxyribonucleotide biosynthesis
Formyltetrahydroformate biosynthesis
Pathway Interaction Database E2F transcription factor network
PathWhiz Pathway Pyrimidine Metabolism
Reactome E2F mediated regulation of DNA replication
Pyrimidine biosynthesis
G1/S-Specific Transcription
WikiPathways Trans-sulfuration and one carbon metabolism
Retinoblastoma (RB) in Cancer
One Carbon Metabolism
Integrated Pancreatic Cancer Pathway
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in leukocytes - TarBase
miR-targeted genes in epithelium - TarBase
Metabolism of nucleotides
Fluoropyrimidine Activity
References
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REF 6Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer. 2011 Oct;74(1):132-8.
REF 7Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009 Jul 3.
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REF 9(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7403).
REF 10FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 074311.
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REF 12ClinicalTrials.gov (NCT00012324) Nolatrexed Dihydrochloride Compared With Doxorubicin in Treating Patients With Recurrent or Unresectable Liver Cancer. U.S. National Institutes of Health.
REF 13Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2013 May;8(5):619-23.
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REF 15ClinicalTrials.gov (NCT00198133) Phase II Study of Alimta (Pemetrexed) Treatment of Advanced Thymoma and Thymic Carcinoma. U.S. National Institutes of Health.
REF 16A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer. Br J Cancer. 2008 Sep 2;99(5):722-6.
REF 17ClinicalTrials.gov (NCT00248404) NB1011 Administered by Continuous Infusion in Cancers That Overexpress Thymidylate Synthase (TS). U.S. National Institutes of Health.
REF 18ClinicalTrials.gov (NCT02171221) Phase I Study of Oral DFP-11207 in Solid Tumors. U.S. National Institutes of Health.
REF 19Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9. Epub 2005 Jul 12.
REF 20Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002454)
REF 21Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002535)
REF 22Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003064)
REF 23Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002433)
REF 24Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003304)
REF 25Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004963)
REF 26Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019549)
REF 27How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 28J Med Chem. 2010 Sep 23;53(18):6539-49.Novel approaches for targeting thymidylate synthase to overcome the resistance and toxicity of anticancer drugs.
REF 29DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
REF 30J 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.
REF 31The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 32Thymidylate 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.
REF 33Association 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.
REF 34The 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. Epub2003 Dec 20.
REF 35Acquisition of resistance to anticancer agents by overproduction of target enzymes. Nippon Rinsho. 1997 May;55(5):1030-7.
REF 36Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion. Clin Cancer Res. 1996 Oct;2(10):1685-92.
REF 37UGT1A7 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.
REF 38J 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.
REF 39National Cancer Institute Drug Dictionary (drug id 762603).
REF 40Folate analogues. 32. Synthesis and biological evaluation of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid and related compounds. J Med Chem. 1989 Jun;32(6):1284-9.
REF 41Antitumor activity of fluoropyrimidines and thymidylate synthetase inhibition. Jpn J Cancer Res. 1991 Apr;82(4):476-82.
REF 42Antisense 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.
REF 43Selective protection by uridine of growth inhibition by 5-fluorouracil (5FU) mediated by 5FU incorporation into RNA, but not the thymidylate synthase mediated growth inhibition by 5FU-leucovorin. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):733-9.
REF 44The role of thymidylate synthase in cellular regulation. Adv Enzyme Regul. 1996;36:143-63.
REF 45Loss 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.
REF 46Evaluating 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.
REF 47Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Mol Cancer Ther. 2009 Apr 21.
REF 48A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration. Br J Cancer. 1999 Feb;79(5-6):915-20.
REF 49J 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.
REF 50Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40.
REF 51Cooperative 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.
REF 52J 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).
REF 53Cellular 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.
REF 54DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96. Epub 2008 Aug 19.
REF 55Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703.
REF 56TECHNOLOGY, PRODUCTS, MARKETS AND SERVICE OPPORTUNITIES. Future Oncology. AUGUST 1995. VOLUME 1, NUMBER 4.
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REF 58Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase. Cancer. 1989 Mar 15;63(6 Suppl):1008-12.
REF 59Kinetic properties of human thymidylate synthase, an anticancer drug target. Biochem Biophys Res Commun. 2003 Jul 25;307(2):297-300.

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