Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTYZVDJ)

• DTT Name: Dihydrofolate reductase (DHFR)
• Synonyms: DYR; DHFRP1
• Gene Name: DHFR
• DTT Type: Successful target; [1]
• BioChemical Class: CH-NH donor oxidoreductase
• UniProt ID: DYR_HUMAN
• TTD ID: T17345
• EC Number: EC 1.5.1.3
• Sequence:
  MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
  IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
  VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
  EVYEKND
• Function: Contributes to the de novo 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 DHFR2. Key enzyme in folate metabolism.
• KEGG Pathway:
  One carbon pool by folate (hsa00670)
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
  Metabolism of folate and pterines (R-HSA-196757)
  G1/S-Specific Transcription (R-HSA-69205)
  E2F mediated regulation of DNA replication (R-HSA-113510)
• BioCyc Pathway: MetaCyc:HS09699-MON

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminosalicylic Acid	DMENSL5	Crohn disease	DD70	Approved	[1]
Leucovorin Calcium	DMNWZJG	Solid tumour/cancer	2A00-2F9Z	Approved	[2]
Methotrexate Sodium	DM5XH2C	Solid tumour/cancer	2A00-2F9Z	Approved	[1]
Trimethoprim	DMM7CHK	Acute otitis media	AB00	Approved	[1]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Iclaprim	DM7YNV9	Bacterial infection	1A00-1C4Z	Phase 3	[3]
CH-4051	DMLQRYH	Rheumatoid arthritis	FA20	Phase 2	[4]
PIRITREXIM	DM276N1	Bladder cancer	2C94	Phase 2	[5]
L-MDAM	DMU901D	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
MDAM (y-methylene-10-deazaaminopterin)	DM1DISM	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
VYR 006	DMC9N7D	Toxoplasmosis	1F57	Phase 1	[8]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TNP-351	DMW05DS	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[9]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1954U89	DM503DN	Solid tumour/cancer	2A00-2F9Z	Preclinical	[10]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Dihydrofolate reductase (DHFR) DME Info
• Gene Name: DHFR

2 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Folic Acid	DMEMBJC	Colorectal carcinoma		Approved	[11]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[12]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [2] Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates.NCI Monogr.1987;(5):17-26.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthritis. IDrugs. 2010 Aug;13(8):559-67.
• [5] Structural variations of piritrexim, a lipophilic inhibitor of human dihydrofolate reductase: synthesis, antitumor activity and molecular modeling ... Eur J Med Chem. 2004 Dec;39(12):1079-88.
• [6] Polyglutamylation of the dihydrofolate reductase inhibitor gamma-methylene-10-deazaaminopterin is not essential for antitumor activity. Clin Cancer Res. 1996 Apr;2(4):707-12.
• [7] Evaluation of the importance of hydrophobic interactions in drug binding to dihydrofolate reductase. J Med Chem. 1988 Jan;31(1):129-37.
• [8] Clinical pipeline report, company report or official report of Vyera Pharmaceuticals.
• [9] A 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.
• [10] The 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.
• [11] The dihydrofolate reductase 19 bp polymorphism is not associated with biomarkers of folate status in healthy young adults, irrespective of folic acid intake. J Nutr. 2015 Oct;145(10):2207-11.
• [12] The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4.