Target Information

Target General Information

Top

Target ID

T52227 (Former ID: TTDS00301)

Target Name

Candida Thymidylate synthase (Candi TMP1)

Synonyms

Tsase of Candida albicans; TS of Candida albicans; TMP1; Human recombinant thymidylate synthase; HrTS

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Gene Name

Candi TMP1

Target Type

Successful target

[1]

Disease

[+] 9 Target-related Diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Colon cancer [ICD-11: 2B90]

Colorectal cancer [ICD-11: 2B91]

Endocarditis [ICD-11: BB40-BA42]

Gram-positive bacterial infection [ICD-11: 1B74-1F40]

Pleural mesothelioma [ICD-11: 2C26]

Rectum cancer [ICD-11: 2B92]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Virus infection [ICD-11: 1A24-1D9Z]

Function

Contributes to thede novo mitochondrial thymidylate biosynthesis pathway.

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BioChemical Class

Methyltransferase

UniProt ID

TYSY_CANAL

EC Number

EC 2.1.1.45

Sequence

MTVSPNTAEQAYLDLCKRIIDEGEHRPDRTGTGTKSLFAPPQLRFDLSNDTFPLLTTKKV
FSKGIIHELLWFVAGSTDAKILSEKGVKIWEGNGSREFLDKLGLTHRREGDLGPVYGFQW
RHFGAEYKDCDSDYTGQGFDQLQDVIKKLKTNPYDRRIIMSAWNPPDFAKMALPPCHVFC
QFYVNFPTSSPDPNNPKQAKTAKPKLSCLLYQRSCDMGLGVPFNIASYALLTKMIAHVVD
MDCGEFIHTLGDAHVYLDHIDALKEQFERIPKQFPKLVIKEERKNEIKSIDDFKFEDFEI
VGYEPYPPIKMKMSV

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Drugs and Modes of Action

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Approved Drug(s)

[+] 9 Approved Drugs

Capecitabine

Drug Info

Approved

Colorectal cancer

[2], [3]

Ciprofloxacin XR

Drug Info

Approved

Bacterial infection

[4]

Floxuridine

Drug Info

Approved

Solid tumour/cancer

[4], [5]

Flucytosine

Drug Info

Approved

Endocarditis

[4], [6]

Fluorouracil

Drug Info

Approved

Solid tumour/cancer

[3]

Leucovorin/5-fluorouracil

Drug Info

Approved

Colon cancer

[3]

Pemetrexed

Drug Info

Approved

Malignant pleural mesothelioma

[4], [7], [8], [9], [10]

Raltitrexed

Drug Info

Approved

Rectal adenocarcinoma

[11], [3]

Trifluridine

Drug Info

Approved

Virus infection

[12], [13]

Clinical Trial Drug(s)

[+] 6 Clinical Trial Drugs

Nolatrexed

Drug Info

Phase 3

Solid tumour/cancer

[14]

Plevitrexed

Drug Info

Phase 2

Gastric adenocarcinoma

[15], [16]

Plevitrexed (R)-isomer

Drug Info

Phase 2

Gastric adenocarcinoma

[16]

UFT/leucovorin calcium

Drug Info

Phase 2

Colorectal cancer

[17]

NB1011

Drug Info

Phase 1/2

Breast cancer

[18]

DFP-11207

Drug Info

Phase 1

Solid tumour/cancer

[19]

Discontinued Drug(s)

[+] 7 Discontinued Drugs

EMITEFUR

Drug Info

Discontinued in Preregistration

Solid tumour/cancer

[20]

Galocitabine

Drug Info

Discontinued in Phase 3

Solid tumour/cancer

[21]

FO-152

Drug Info

Discontinued in Phase 2

Solid tumour/cancer

[22]

TT-62

Drug Info

Discontinued in Phase 2

Virus infection

[23]

AG-331

Drug Info

Discontinued in Phase 1

Solid tumour/cancer

[24]

DMPDDF

Drug Info

Terminated

Solid tumour/cancer

[25]

Fosfluridine tidoxil

Drug Info

Terminated

Keratosis

[26]

Mode of Action

[+] 3 Modes of Action

Inhibitor

[+] 51 Inhibitor drugs

Capecitabine

Drug Info

[27]

Ciprofloxacin XR

Drug Info

[28]

Floxuridine

Drug Info

[29]

Flucytosine

Drug Info

[6]

Fluorouracil

Drug Info

[30], [31], [32], [33]

Leucovorin/5-fluorouracil

Drug Info

[34], [35]

Pemetrexed

Drug Info

[1]

Raltitrexed

Drug Info

[36], [37]

Trifluridine

Drug Info

[38]

Nolatrexed

Drug Info

[39]

Plevitrexed

Drug Info

[40]

Plevitrexed (R)-isomer

Drug Info

[40]

DFP-11207

Drug Info

[43]

EMITEFUR

Drug Info

[44]

Galocitabine

Drug Info

[45]

TT-62

Drug Info

[47]

AG-331

Drug Info

[48]

DMPDDF

Drug Info

[49]

Fosfluridine tidoxil

Drug Info

[50]

(6s)-5,6,7,8-Tetrahydrofolate

Drug Info

[51]

1,3-propanediphosphonic acid

Drug Info

[52]

1,4-Dithiothreitol

Drug Info

[51]

10-Propargyl-5,8-Dideazafolic Acid

Drug Info

[51]

2'-5'dideoxyuridine

Drug Info

[53]

2'-Deoxycytidine-5'-Monophosphate

Drug Info

[51]

2'-Deoxyguanosine-5'-Monophosphate

Drug Info

[51]

2'-Deoxyuridine

Drug Info

[51]

2'-deoxyuridylic acid

Drug Info

[51]

2-bromophenol

Drug Info

[53]

2-Sulfhydryl-Ethanol

Drug Info

[51]

3-Amino-5,6-dihydro-2H-benzo[f]quinazolin-1-one

Drug Info

[54]

3-DIPHENOL-6-NITRO-3H-BENZO[DE]ISOCHROMEN-1-ONE

Drug Info

[55]

3-Methyl-2H-benzo[f]quinazolin-1-one

Drug Info

[54]

4-CHLORO-3',3''-DIBROMOPHENOL-1,8-NAPHTHALEIN

Drug Info

[53]

5,10-Methylene-6-Hydrofolic Acid

Drug Info

[51]

5-Fluoro-2'-Deoxyuridine-5'-Monophosphate

Drug Info

[51]

6-ETHYL-5-PHENYLPYRIMIDINE-2,4-DIAMINE

Drug Info

[55]

Ly231514 Tetra Glu

Drug Info

[51]

LY341770

Drug Info

[51]

Methionine Sulfoxide

Drug Info

[55]

N,O-Didansyl-L-Tyrosine

Drug Info

[51]

N-Carboxymethionine

Drug Info

[51]

N-[Tosyl-D-Prolinyl]Amino-Ethanethiol

Drug Info

[51]

PREMETREXED

Drug Info

[56]

S,S-(2-Hydroxyethyl)Thiocysteine

Drug Info

[51]

Sp-722

Drug Info

[51]

Sp-876

Drug Info

[51]

Thymidine-5'-Phosphate

Drug Info

[51]

Tosyl-D-Proline

Drug Info

[51]

Uridine-5'-Monophosphate

Drug Info

[51]

ZD1604

Drug Info

[33]

Modulator

[+] 3 Modulator drugs

UFT/leucovorin calcium

Drug Info

[41]

FO-152

Drug Info

[46]

OVI-117

Drug Info

[46]

Binder

[+] 1 Binder drugs

NB1011

Drug Info

[42]

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Similarity Proteins

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Similarity Proteins

There is no similarity protein (E value < 0.005) for this target

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Profiles in Patients

Top

Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways

Top

BioCyc

[+] 6 BioCyc Pathways

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

[+] 3 KEGG Pathways

Pyrimidine metabolism

One carbon pool by folate

Metabolic pathways

Panther Pathway

[+] 2 Panther Pathways

De novo pyrimidine deoxyribonucleotide biosynthesis

Formyltetrahydroformate biosynthesis

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Pyrimidine Metabolism

PID Pathway

[+] 1 PID Pathways

E2F transcription factor network

Reactome

[+] 3 Reactome Pathways

E2F mediated regulation of DNA replication

Pyrimidine biosynthesis

G1/S-Specific Transcription

WikiPathways

[+] 10 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

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

Target QSAR Model

References

Top

REF 1

Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40.

REF 2

URL: 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 3

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

REF 6

Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9.

REF 7

REF 8

Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009 Nov;66(2):141-9.

REF 9

2004 approvals: the demise of the blockbuster. Nat Rev Drug Discov. 2005 Feb;4(2):93-4.

REF 10

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 11

REF 12

REF 13

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 074311.

REF 14

ClinicalTrials.gov (NCT00012324) Nolatrexed Dihydrochloride Compared With Doxorubicin in Treating Patients With Recurrent or Unresectable Liver Cancer. U.S. National Institutes of Health.

REF 15

REF 16

Clinical pipeline report, company report or official report of plevitrexed.

REF 17

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 18

ClinicalTrials.gov (NCT00248404) NB1011 Administered by Continuous Infusion in Cancers That Overexpress Thymidylate Synthase (TS). U.S. National Institutes of Health.

REF 19

ClinicalTrials.gov (NCT02171221) Phase I Study of Oral DFP-11207 in Solid Tumors. U.S. National Institutes of Health.

REF 20

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 21

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 22

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 23

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 24

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 25

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 26

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019549)

REF 27

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 28

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 29

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 30

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.

REF 31

Association of gastric and intestinal phenotypic marker expression of gastric carcinomas with tumor thymidylate synthase expression and response to... J Cancer Res Clin Oncol. 2003 Dec;129(12):683-90.

REF 32

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 33

Acquisition of resistance to anticancer agents by overproduction of target enzymes. Nippon Rinsho. 1997 May;55(5):1030-7.

REF 34

Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Mol Cancer Ther. 2009 May;8(5):1037-44.

REF 35

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.

REF 36

DNA damage and homologous recombination signaling induced by thymidylate deprivation. Biochem Pharmacol. 2008 Oct 15;76(8):987-96.

REF 37

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 38

Trifluorothymidine induces cell death independently of p53. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):699-703.

REF 39

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 40

Cooperative inhibition of human thymidylate synthase by mixtures of active site binding and allosteric inhibitors. Biochemistry. 2007 Mar 13;46(10):2823-30.

REF 41

Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase. Cancer. 1989 Mar 15;63(6 Suppl):1008-12.

REF 42

Kinetic properties of human thymidylate synthase, an anticancer drug target. Biochem Biophys Res Commun. 2003 Jul 25;307(2):297-300.

REF 43

National Cancer Institute Drug Dictionary (drug id 762603).

REF 44

Antitumor activity of fluoropyrimidines and thymidylate synthetase inhibition. Jpn J Cancer Res. 1991 Apr;82(4):476-82.

REF 45

The role of thymidylate synthase in cellular regulation. Adv Enzyme Regul. 1996;36:143-63.

REF 46

REF 47

TECHNOLOGY, PRODUCTS, MARKETS AND SERVICE OPPORTUNITIES. Future Oncology. AUGUST 1995. VOLUME 1, NUMBER 4.

REF 48

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 49

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 50

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 51

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 52

Novel approaches for targeting thymidylate synthase to overcome the resistance and toxicity of anticancer drugs. J Med Chem. 2010 Sep 23;53(18):6539-49.

REF 53

DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.

REF 54

Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some sulfonamidobenzoylglutamate and related de... J Med Chem. 1993 Oct 29;36(22):3464-71.

REF 55

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 56

Dual inhibitors of thymidylate synthase and dihydrofolate reductase as antitumor agents: design, synthesis, and biological evaluation of classical ... J Med Chem. 2006 Feb 9;49(3):1055-65.

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