Target General Infomation
Target ID
T89515
Former ID
TTDS00208
Target Name
Dihydrofolate reductase
Gene Name
PDF
Synonyms
PDF
Target Type
Successful
Disease Advanced cancers [ICD9: 140-229; ICD10: C00-C96]
Gram-positive bacterial infection [ICD9: 001-009, 010-018, 020-027, 030-041, 080-088, 090-099, 100-104]
Leukemia [ICD9: 208.9; ICD10: C90-C95]
Malaria [ICD10: B54]
Malaria; Anxiety disorder [ICD9:300, 311; ICD10: B54, F32, F40-F42]
Peripheral T-cell lymphoma; Breast cancer [ICD9:202.7, 174, 175; ICD10: C84.4, C50]
Toxoplasmosis; Pneumocystis carinii pneumonia [ICD10: B58]
Function
Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.
BioChemical Class
Oxidoreductases acting on CH-NH group of donors
Target Validation
T89515
UniProt ID
EC Number
EC 1.5.1.3
Sequence
MARLWGALSLWPLWAAVPWGGAAAVGVRACSSTAAPDGVEGPALRRSYWRHLRRLVLGPP
EPPFSHVCQVGDPVLRGVAAPVERAQLGGPELQRLTQRLVQVMRRRRCVGLSAPQLGVPR
QVLALELPEALCRECPPRQRALRQMEPFPLRVFVNPSLRVLDSRLVTFPEGCESVAGFLA
CVPRFQAVQISGLDPNGEQVVWQASGWAARIIQHEMDHLQGCLFIDKMDSRTFTNVYWMK
VND
Drugs and Mode of Action
Drug(s) Chlorproguanil Drug Info Approved Malaria [536602]
MCB-3837 Drug Info Approved Malaria [536773]
Pralatrexate Drug Info Approved Peripheral T-cell lymphoma; Breast cancer [530677], [541920], [551871]
Proguanil Drug Info Approved Malaria [536135]
Proquanil Drug Info Approved Malaria; Anxiety disorder [536602], [551871]
Trimetrexate Drug Info Approved Toxoplasmosis; Pneumocystis carinii pneumonia [551871]
Metoprine Drug Info Phase 2 Advanced cancers [523875], [542436]
PREMETREXED Drug Info Phase 2 Discovery agent [521700]
Aminopterin Drug Info Withdrawn from market Leukemia [550114]
Inhibitor 2'-Monophosphoadenosine 5'-Diphosphoribose Drug Info [551393]
2'-Monophosphoadenosine-5'-Diphosphate Drug Info [551393]
2,4-diamino triazine Drug Info [537892]
2-(N-Morpholino)-Ethanesulfonic Acid Drug Info [551393]
2-Allylthio-3-benzyl-6-nitro-quinazolin-4(3H)-one Drug Info [530816]
2-Allylthio-6-amino-3-benzyl-quinazolin-4(3H)-one Drug Info [530816]
3-Benzyl-2-ethylthio-6-nitro-quinazolin-4(3H)-one Drug Info [530816]
3-benzyl-2-mercapto-6-nitroquinazolin-4(3H)-one Drug Info [530816]
3-Phenylsulfanylmethyl-quinoxaline-5,7-diamine Drug Info [533598]
4-(2,6-diamino-9H-purin-8-yl)-2,6-dimethoxyphenol Drug Info [530674]
5,10-Dideazatetrahydrofolic Acid Drug Info [551393]
5-((E)-Styryl)-quinazoline-2,4-diamine Drug Info [533781]
5-(2-fluorobenzyloxy)quinazoline-2,4-diamine Drug Info [529261]
5-(4-Methoxyphenoxy)-2,4-Quinazolinediamine Drug Info [551393]
5-Chloryl-2,4,6-Quinazolinetriamine Drug Info [551393]
5-Formyl-6-Hydrofolic Acid Drug Info [551393]
5-p-Tolylsulfanyl-quinazoline-2,4-diamine Drug Info [526126]
5-Phenethyl-quinazoline-2,4-diamine Drug Info [533781]
5-Phenylsulfanyl-2,4-Quinazolinediamine Drug Info [551393]
5-Phenylsulfanyl-quinazoline-2,4-diamine Drug Info [526126]
6,7-Diphenyl-pteridine-2,4-diamine Drug Info [526601]
6-(2-Phenylsulfanyl-ethyl)-pteridine-2,4-diamine Drug Info [526601]
6-m-Tolyl-pteridine-2,4,7-triamine Drug Info [526601]
6-Phenylaminomethyl-quinazoline-2,4-diamine Drug Info [526679]
6-Phenylsulfanylmethyl-pteridine-2,4-diamine Drug Info [534121]
7-Methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine Drug Info [534126]
7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine Drug Info [534126]
8-(2,3,4-trimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(2,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(2,4,6-trimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(2,4-dimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(2,5-dimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(2,6-Dichloro-phenyl)-9H-purine-2,6-diamine Drug Info [534468]
8-(3,4,5-trimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(3,4-dichlorophenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(3,4-dimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-(3,5-dimethoxyphenyl)-9H-purine-2,6-diamine Drug Info [530674]
8-benzyl-9H-purine-2,6-diamine Drug Info [530674]
8-Pyridin-4-yl-9H-purine-2,6-diamine Drug Info [534468]
Aminopterin Drug Info [535644], [535830]
Beta-Mercaptoethanol Drug Info [551393]
Biopterin Drug Info [551393]
Br-WR99210 Drug Info [534947]
Brodimoprim-4,6-Dicarboxylate Drug Info [551393]
Bromo-WR99210 Drug Info [551393]
CB-3717 Drug Info [530351]
Chlorproguanil Drug Info [536602]
Cycloguanil Drug Info [536135]
Derivative of methotrexate Drug Info [533568]
Dihydrofolic Acid Drug Info [551393]
Edatrexate Drug Info [535644]
Furo[2,3d]Pyrimidine Antifolate Drug Info [551393]
GNF-PF-173 Drug Info [532648]
GNF-PF-607 Drug Info [527455]
MCB-3837 Drug Info [536602], [536773]
Metoprine Drug Info [536216]
N*6*-Benzyl-quinazoline-2,4,6-triamine Drug Info [527455]
NB-3040 Drug Info [536094]
NB3178 Drug Info [536094]
NB3322 Drug Info [536094]
PDDF Drug Info [527854]
Pergularinine Drug Info [534967]
Pralatrexate Drug Info [530677]
PREMETREXED Drug Info [535186]
Proguanil Drug Info [538065]
Proquanil Drug Info [536602]
Sri-9439 Drug Info [551391]
Sri-9662 Drug Info [551393]
Trimetrexate Drug Info [535058], [538096]
Tylophorinidine Drug Info [534967]
WR99210 Drug Info [535582], [538065]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
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
References
Ref 521700ClinicalTrials.gov (NCT00198133) Phase II Study of Alimta (Pemetrexed) Treatment of Advanced Thymoma and Thymic Carcinoma. U.S. National Institutes of Health.
Ref 523875ClinicalTrials.gov (NCT01579110) Efficacy and Safety of Levamisole Combined With Standard Prednisolone in Warm Antibody Autoimmune Hemolytic Anemia.. U.S. National Institutes of Health.
Ref 530677Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
Ref 536135Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
Ref 536602The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
Ref 536773How many modes of action should an antibiotic have? Curr Opin Pharmacol. 2008 Oct;8(5):564-73. Epub 2008 Jul 30.
Ref 541920(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: 6840).
Ref 542436(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: 7412).
Ref 550114Drug information of Aminopterin, Health Canada, 2007.
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 526126J Med Chem. 2001 Aug 30;44(18):2928-32.X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor.
Ref 526601J Med Chem. 2003 Apr 24;46(9):1726-36.Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS.
Ref 526679J Med Chem. 2003 Jul 31;46(16):3455-62.Design and synthesis of dihydrofolate reductase inhibitors encompassing a bridging ester group. Evaluation in a mouse colitis model.
Ref 527455J Med Chem. 2005 Mar 10;48(5):1448-69.CoMFA and CoMSIA analyses of Pneumocystis carinii dihydrofolate reductase, Toxoplasma gondii dihydrofolate reductase, and rat liver dihydrofolate reductase.
Ref 527854J 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 529261J Med Chem. 2008 Feb 14;51(3):449-69. Epub 2008 Jan 19.Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy.
Ref 530351J 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 530674Bioorg Med Chem. 2010 Feb 15;18(4):1684-701. Epub 2010 Jan 6.CoMFA analysis of tgDHFR and rlDHFR based on antifolates with 6-5 fused ring system using the all-orientation search (AOS) routine and a modified cross-validated r(2)-guided region selection (q(2)-GRS) routine and its initial application.
Ref 530677Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
Ref 530816Bioorg Med Chem. 2010 Apr 15;18(8):2849-63. Epub 2010 Mar 12.Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones.
Ref 532648J Med Chem. 1988 Jan;31(1):181-5.Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin.
Ref 533568J Med Chem. 1982 Feb;25(2):182-7.Syntheses of alpha- and gamma-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism.
Ref 533598J Med Chem. 1995 Nov 24;38(24):4739-59.New drug developments for opportunistic infections in immunosuppressed patients: Pneumocystis carinii.
Ref 533781J Med Chem. 1995 Mar 3;38(5):745-52.2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii.
Ref 534121J Med Chem. 1996 Apr 26;39(9):1836-45.Nonclassical 2,4-diamino-8-deazafolate analogues as inhibitors of dihydrofolate reductases from rat liver, Pneumocystis carinii, and Toxoplasma gondii.
Ref 534126J Med Chem. 1996 Feb 16;39(4):892-903.High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size.
Ref 534468J Med Chem. 1997 Sep 12;40(19):3032-9.Conformationally restricted analogues of trimethoprim: 2,6-diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneumocystis carinii and Toxoplasma gondii.
Ref 534947Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs. J Mol Biol. 2000 Jan 14;295(2):307-23.
Ref 534967Inhibition of dihydrofolate reductase and cell growth activity by the phenanthroindolizidine alkaloids pergularinine and tylophorinidine: the in vitro cytotoxicity of these plant alkaloids and their potential as antimicrobial and anticancer agents. Toxicol In Vitro. 2000 Feb;14(1):53-9.
Ref 535058Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase. Antimicrob Agents Chemother. 2000 Nov;44(11):3092-6.
Ref 535186Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. J Med Chem. 2001 Jun 7;44(12):1993-2003.
Ref 535582Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase. Antimicrob Agents Chemother. 2002 Nov;46(11):3362-9.
Ref 535644Loss 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 535830vestigial suppressor genes and resistance to aminopterin in Drosophila melanogaster. Heredity. 1992 Nov;69 ( Pt 5):473-7.
Ref 536094Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
Ref 536135Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
Ref 536216Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34. Epub 2006 Apr 13.
Ref 536602The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
Ref 536773How many modes of action should an antibiotic have? Curr Opin Pharmacol. 2008 Oct;8(5):564-73. Epub 2008 Jul 30.
Ref 537892Ab initio studies of 2,4-diamino triazine and its complexes with ligands: a model for inhibitor-active site interactions of dihydrofolate reductase. Cancer Invest. 1994;12(5):469-76.
Ref 538065Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6.
Ref 538096Synthesis and biological activities of tricyclic conformationally restricted tetrahydropyrido annulated furo[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases. J Med Chem. 1998 Apr 23;41(9):1409-16.
Ref 551391DrugBank 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 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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