Target Information
Target General Infomation | |||||
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Target ID |
T52227
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Former ID |
TTDS00301
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Target Name |
Thymidylate synthase
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Gene Name |
TMP1
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Synonyms |
HrTS; Human recombinant thymidylate synthase; OK/SW-cl.29; TS; TSase; TMP1
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Target Type |
Successful
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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.
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BioChemical Class |
Methyltransferase superfamily
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Target Validation |
T52227
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UniProt ID | |||||
EC Number |
EC 2.1.1.45
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Sequence |
MTVSPNTAEQAYLDLCKRIIDEGEHRPDRTGTGTKSLFAPPQLRFDLSNDTFPLLTTKKV
FSKGIIHELLWFVAGSTDAKILSEKGVKIWEGNGSREFLDKLGLTHRREGDLGPVYGFQW RHFGAEYKDCDSDYTGQGFDQLQDVIKKLKTNPYDRRIIMSAWNPPDFAKMALPPCHVFC QFYVNFPTSSPDPNNPKQAKTAKPKLSCLLYQRSCDMGLGVPFNIASYALLTKMIAHVVD MDCGEFIHTLGDAHVYLDHIDALKEQFERIPKQFPKLVIKEERKNEIKSIDDFKFEDFEI VGYEPYPPIKMKMSV |
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Drugs and Mode of Action | |||||
Drug(s) | Capecitabine | Drug Info | Approved | Colorectal cancer | [536361], [541880] |
Floxuridine/5-fluorouracil | Drug Info | Approved | Colorectal cancer | [536361] | |
Flucytosine | Drug Info | Approved | Endocarditis | [536275], [551871] | |
Fluorouracil | Drug Info | Approved | Cancer | [536361] | |
Leucovorin/5-fluorouracil | Drug Info | Approved | Colon cancer | [536361] | |
Pemetrexed | Drug Info | Approved | Malignant pleural mesothelioma | [527466], [531376], [537580], [541917], [551871] | |
Raltitrexed | Drug Info | Approved | Colon cancer; Rectal cancer | [536361], [542426] | |
Trifluridine | Drug Info | Approved | Viral infections | [538271], [543253] | |
Capecitabine | Drug Info | Phase 3 | Breast cancer | [536361], [541880] | |
Nolatrexed | Drug Info | Phase 3 | Solid tumours | [521484] | |
Plevitrexed | Drug Info | Phase 2 | Advanced gastric cancer | [532289], [543033] | |
Plevitrexed (R)-isomer | Drug Info | Phase 2 | Advanced gastric cancer | [532289] | |
PREMETREXED | Drug Info | Phase 2 | Discovery agent | [521700] | |
UFT/leucovorin calcium | Drug Info | Phase 2 | Colorectal cancer | [529654] | |
NB1011 | Drug Info | Phase 1/2 | Breast cancer | [521754] | |
DFP-11207 | Drug Info | Phase 1 | Solid tumours | [524804] | |
GW1843 | Drug Info | Phase 1 | Biliary cancer | [527633] | |
EMITEFUR | Drug Info | Discontinued in Preregistration | Solid tumours | [545208] | |
GALOCITABINE | Drug Info | Discontinued in Phase 3 | Solid tumours | [545231] | |
FO-152 | Drug Info | Discontinued in Phase 2 | Cancer | [545375] | |
TT-62 | Drug Info | Discontinued in Phase 2 | Viral infections | [545197] | |
AG-331 | Drug Info | Discontinued in Phase 1 | Solid tumours | [545448] | |
DMPDDF | Drug Info | Terminated | Cancer | [545832] | |
Fosfluridine tidoxil | Drug Info | Terminated | Keratosis | [547816] | |
Inhibitor | (6s)-5,6,7,8-Tetrahydrofolate | Drug Info | [551393] | ||
1,3-propanediphosphonic acid | Drug Info | [530956] | |||
1,4-Dithiothreitol | Drug Info | [551393] | |||
10-Propargyl-5,8-Dideazafolic Acid | Drug Info | [551393] | |||
2'-5'dideoxyuridine | Drug Info | [551391] | |||
2'-Deoxycytidine-5'-Monophosphate | Drug Info | [551393] | |||
2'-Deoxyguanosine-5'-Monophosphate | Drug Info | [551393] | |||
2'-Deoxyuridine | Drug Info | [551393] | |||
2'-deoxyuridylic acid | Drug Info | [551393] | |||
2-bromophenol | Drug Info | [551391] | |||
3-Amino-5,6-dihydro-2H-benzo[f]quinazolin-1-one | Drug Info | [533943] | |||
3-DIPHENOL-6-NITRO-3H-BENZO[DE]ISOCHROMEN-1-ONE | Drug Info | [551374] | |||
3-Methyl-2H-benzo[f]quinazolin-1-one | Drug Info | [533943] | |||
4-CHLORO-3',3''-DIBROMOPHENOL-1,8-NAPHTHALEIN | Drug Info | [551391] | |||
5,10-Methylene-6-Hydrofolic Acid | Drug Info | [551393] | |||
5-Fluoro-2'-Deoxyuridine-5'-Monophosphate | Drug Info | [551393] | |||
5-Fluorouracil | Drug Info | [534992], [535857], [535884], [538032] | |||
6-ETHYL-5-PHENYLPYRIMIDINE-2,4-DIAMINE | Drug Info | [551374] | |||
AG-331 | Drug Info | [534748] | |||
Beta-Mercaptoethanol | Drug Info | [551393] | |||
Capecitabine | Drug Info | [536046] | |||
CB-3717 | Drug Info | [530351] | |||
DFP-11207 | Drug Info | [550515] | |||
DMPDDF | Drug Info | [533040] | |||
EMITEFUR | Drug Info | [529831] | |||
Floxuridine/5-fluorouracil | Drug Info | [534899] | |||
Flucytosine | Drug Info | [536275] | |||
Fluorouracil | Drug Info | [534992], [535857], [535884], [538032] | |||
Fosfluridine tidoxil | Drug Info | [529580] | |||
GALOCITABINE | Drug Info | [534250] | |||
GW1843 | Drug Info | [535644] | |||
Leucovorin/5-fluorouracil | Drug Info | [536699], [537251] | |||
Ly231514 Tetra Glu | Drug Info | [551393] | |||
LY341770 | Drug Info | [551393] | |||
N,O-Didansyl-L-Tyrosine | Drug Info | [551393] | |||
N-Carboxymethionine | Drug Info | [551393] | |||
N-[Tosyl-D-Prolinyl]Amino-Ethanethiol | Drug Info | [551393] | |||
Nolatrexed | Drug Info | [525434] | |||
PDDF | Drug Info | [527854] | |||
Pemetrexed | Drug Info | [537219] | |||
Plevitrexed | Drug Info | [536356] | |||
Plevitrexed (R)-isomer | Drug Info | [536356] | |||
PREMETREXED | Drug Info | [528001] | |||
Raltitrexed | Drug Info | [534940], [536842] | |||
S,S-(2-Hydroxyethyl)Thiocysteine | Drug Info | [551393] | |||
S-Oxymethionine | Drug Info | [551374] | |||
Sp-722 | Drug Info | [551393] | |||
Sp-876 | Drug Info | [551393] | |||
Thymidine-5'-Phosphate | Drug Info | [551393] | |||
Tosyl-D-Proline | Drug Info | [551393] | |||
Trifluridine | Drug Info | [536764] | |||
TT-62 | Drug Info | [551465] | |||
Uridine-5'-Monophosphate | Drug Info | [551393] | |||
ZD1604 | Drug Info | [538032] | |||
Modulator | FO-152 | Drug Info | [543675] | ||
OVI-117 | Drug Info | [543675] | |||
UFT/leucovorin calcium | Drug Info | [532956] | |||
Binder | NB1011 | Drug Info | [535765] | ||
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 | |||||
Ref 521484 | ClinicalTrials.gov (NCT00012324) Nolatrexed Dihydrochloride Compared With Doxorubicin in Treating Patients With Recurrent or Unresectable Liver Cancer. U.S. National Institutes of Health. | ||||
Ref 521700 | ClinicalTrials.gov (NCT00198133) Phase II Study of Alimta (Pemetrexed) Treatment of Advanced Thymoma and Thymic Carcinoma. U.S. National Institutes of Health. | ||||
Ref 521754 | ClinicalTrials.gov (NCT00248404) NB1011 Administered by Continuous Infusion in Cancers That Overexpress Thymidylate Synthase (TS). U.S. National Institutes of Health. | ||||
Ref 524804 | ClinicalTrials.gov (NCT02171221) Phase I Study of Oral DFP-11207 in Solid Tumors. U.S. National Institutes of Health. | ||||
Ref 527633 | Low 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 529654 | A 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 531376 | Thymidylate 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 532289 | Phase 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. | ||||
Ref 536275 | Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9. | ||||
Ref 536361 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20. | ||||
Ref 537580 | Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009 Jul 3. | ||||
Ref 538271 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 074311. | ||||
Ref 541880 | (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: 6799). | ||||
Ref 541917 | (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: 6837). | ||||
Ref 542426 | (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 543033 | (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: 8278). | ||||
Ref 543253 | (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: 8697). | ||||
Ref 545197 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002433) | ||||
Ref 545208 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002454) | ||||
Ref 545231 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002535) | ||||
Ref 545375 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003064) | ||||
Ref 545448 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003304) | ||||
Ref 545832 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004963) | ||||
Ref 525434 | A 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 527854 | 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. | ||||
Ref 528001 | 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). | ||||
Ref 529580 | Selective 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 529831 | Antitumor activity of fluoropyrimidines and thymidylate synthetase inhibition. Jpn J Cancer Res. 1991 Apr;82(4):476-82. | ||||
Ref 530351 | 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. | ||||
Ref 530956 | 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. | ||||
Ref 532956 | Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase. Cancer. 1989 Mar 15;63(6 Suppl):1008-12. | ||||
Ref 533040 | Folate 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 533943 | 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. | ||||
Ref 534250 | The role of thymidylate synthase in cellular regulation. Adv Enzyme Regul. 1996;36:143-63. | ||||
Ref 534748 | Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion. Clin Cancer Res. 1996 Oct;2(10):1685-92. | ||||
Ref 534899 | 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. | ||||
Ref 534940 | 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. | ||||
Ref 534992 | 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. | ||||
Ref 535644 | 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. | ||||
Ref 535765 | Kinetic properties of human thymidylate synthase, an anticancer drug target. Biochem Biophys Res Commun. 2003 Jul 25;307(2):297-300. | ||||
Ref 535857 | 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. | ||||
Ref 535884 | 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. Epub2003 Dec 20. | ||||
Ref 536046 | 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. | ||||
Ref 536275 | Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9. | ||||
Ref 536356 | 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. | ||||
Ref 536699 | 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. | ||||
Ref 536764 | Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703. | ||||
Ref 536842 | DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96. Epub 2008 Aug 19. | ||||
Ref 537219 | Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40. | ||||
Ref 537251 | Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Mol Cancer Ther. 2009 Apr 21. | ||||
Ref 538032 | Acquisition of resistance to anticancer agents by overproduction of target enzymes. Nippon Rinsho. 1997 May;55(5):1030-7. | ||||
Ref 543675 | (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. (Target id: 2642). | ||||
Ref 551391 | DrugBank 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 |
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