Target Information

Target General Infomation
Target ID
T17345
Former ID
TTDI00931
Target Name
DHFR
Gene Name
DHFR
Synonyms
Dihydrofolate reductase; DHFR
Target Type
Successful
Disease Bladder cancer [ICD9: 188; ICD10: C67]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Pulmonary and extrapulmonary tuberculosis [ICD10: A15-A19]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Urinary tract infections [ICD9: 599; ICD10: N39.0]
Function
Key enzyme in folate metabolism. Contributes to the denovo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
BioChemical Class
Oxidoreductases acting on CH-NH group of donors
UniProt ID
P00374
EC Number
EC 1.5.1.3
Sequence
MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
EVYEKND
Drugs and Mode of Action
Drug(s) Aminosalicylate Sodium Drug Info Approved Pulmonary and extrapulmonary tuberculosis [551871]
Leucovorin Calcium Drug Info Approved Cancer [551871]
Methotrexate Sodium Drug Info Approved Cancer [551871]
Trimethoprim Drug Info Approved Urinary tract infections [536854]
CH-4051 Drug Info Phase 2 Rheumatoid arthritis [523026]
PIRITREXIM Drug Info Phase 2 Bladder cancer [521445], [542438]
L-MDAM Drug Info Phase 1 Solid tumours [546152]
MDAM (y-methylene-10-deazaaminopterin) Drug Info Phase 1 Cancer [527024]
1954U89 Drug Info Preclinical Solid tumours [534414]
TNP-351 Drug Info Discontinued in Phase 2 Solid tumours [545242]
Methotrexate Sodium Drug Info Investigative Discovery agent [468047]
Modulator 1954U89 Drug Info [534414]
Aminosalicylate Sodium Drug Info [556264]
Leucovorin Calcium Drug Info
Methotrexate Sodium Drug Info [556264]
PIRITREXIM Drug Info
Trimethoprim Drug Info [556264]
Inhibitor CH-4051 Drug Info [531111]
L-MDAM Drug Info [534749]
MDAM (y-methylene-10-deazaaminopterin) Drug Info [533440]
TNP-351 Drug Info [526176]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
DRM DRM Info
Pathways
KEGG Pathway One carbon pool by folate
Folate biosynthesis
Metabolic pathways
PANTHER Pathway Tetrahydrofolate biosynthesis
Formyltetrahydroformate biosynthesis
Pathway Interaction Database E2F transcription factor network
PathWhiz Pathway Folate Metabolism
Pterine Biosynthesis
Reactome E2F mediated regulation of DNA replication
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
Metabolism of folate and pterines
G1/S-Specific Transcription
WikiPathways Nucleotide Metabolism
Trans-sulfuration and one carbon metabolism
Retinoblastoma (RB) in Cancer
One Carbon Metabolism
Metabolism of water-soluble vitamins and cofactors
Metabolism of nitric oxide
Folate Metabolism
Fluoropyrimidine Activity
References
Ref 468047(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: 4815).
Ref 521445ClinicalTrials.gov (NCT00002914) Piritrexim in Treating Patients With Advanced Cancer of the Urinary Tract. U.S. National Institutes of Health.
Ref 523026ClinicalTrials.gov (NCT01116141) A Study of CH-4051 in Patients With Rheumatoid Arthritis (RA). U.S. National Institutes of Health.
Ref 527024Final results of a phase I and pharmacokinetic study of gamma-methylene-10-deazaaminopterin (MDAM) administered intravenously daily for five consecutive days in patients with solid tumors. Cancer Chemother Pharmacol. 2004 May;53(5):370-6. Epub 2003 Dec 18.
Ref 534414The pharmacokinetics of 1954U89, 1,3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3,2-f)quinazoline, in dogs and rats after intravenous and oral administration. Biopharm Drug Dispos. 1997 Jul;18(5):433-42.
Ref 536854Has nature already identified all useful antibacterial targets? Curr Opin Microbiol. 2008 Oct;11(5):387-92. Epub 2008 Oct 6.
Ref 542438(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: 7414).
Ref 545242Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002566)
Ref 546152Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006614)
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 526176A Ring-Transformation/Ring-Annulation Strategy for the Synthesis of the DHFR Inhibitor, TNP-351: A Correction. J Org Chem. 1996 Nov 1;61(22):7973-7974.
Ref 531111CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthritis. IDrugs. 2010 Aug;13(8):559-67.
Ref 533440Evaluation of the importance of hydrophobic interactions in drug binding to dihydrofolate reductase. J Med Chem. 1988 Jan;31(1):129-37.
Ref 534414The pharmacokinetics of 1954U89, 1,3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3,2-f)quinazoline, in dogs and rats after intravenous and oral administration. Biopharm Drug Dispos. 1997 Jul;18(5):433-42.
Ref 534749Polyglutamylation of the dihydrofolate reductase inhibitor gamma-methylene-10-deazaaminopterin is not essential for antitumor activity. Clin Cancer Res. 1996 Apr;2(4):707-12.
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

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