T3DB: Methotrexate

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (11)XML

Targets (11)

Record Information

Version

2.0

Creation Date

2009-07-03 22:10:49 UTC

Update Date

2014-12-24 20:25:35 UTC

Accession Number

T3D2486

Identification

Common Name

Methotrexate

Class

Small Molecule

Description

Methotrexate is only found in individuals that have used or taken this drug. It is an antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [PubChem]Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

Compound Type

Abortifacient Agent
Abortifacient Agent, Nonsteroidal
Amide
Amine
Antimetabolite
Antimetabolite, Antineoplastic
Antineoplastic Agent
Antirheumatic Agent
Dermatologic Agent
Drug
Enzyme Inhibitor
Ester
Folic Acid Antagonist
Immunosuppressive Agent
Metabolite
Nucleic Acid Synthesis Inhibitor
Organic Compound
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
4-amino-10-methylfolic acid
4-amino-N(10)-Methylpteroylglutamic acid
Abitrexate
Alltrex
Amethopterin
Amethopterine
Artrait
Atrexel
Bendatrexat
Carditrex
Dermotrex
Ebetrex
Emtexate
HDMTX
L-Amethopterin
Ledertrexate
Maxtrex
Meisusheng
Methopterin
Methotextrate
Methotrexat
Méthotrexate
Methotrexatum
Methotrexic acid
Methylaminopterin
Methylaminopterinum
Metotrexato
Mexate
MTX
N-Bismethylpteroylglutamic acid
N-[4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid
Otrexup
Rheumatrex
Trexall
Trexan
Zexate

Chemical Formula

C₂₀H₂₂N₈O₅

Average Molecular Mass

454.439 g/mol

Monoisotopic Mass

454.171 g/mol

CAS Registry Number

59-05-2

IUPAC Name

(2S)-2-[(4-{[(2,4-diaminopteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid

Traditional Name

methotrexate

SMILES

[H][C@@](CCC(O)=O)(NC(=O)C1=CC=C(C=C1)N(C)CC1=NC2=C(N)NC(=N)N=C2N=C1)C(O)=O

InChI Identifier

InChI=1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1

InChI Key

InChIKey=FBOZXECLQNJBKD-ZDUSSCGKSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as glutamic acid and derivatives. Glutamic acid and derivatives are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Glutamic acid and derivatives

Alternative Parents

Substituents

Glutamic acid or derivatives
Hippuric acid or derivatives
Hippuric acid
N-acyl-alpha-amino acid
N-acyl-alpha amino acid or derivatives
Aminobenzamide
Aminobenzoic acid or derivatives
Pteridine
Benzamide
Benzoic acid or derivatives
Benzoyl
Aniline or substituted anilines
Tertiary aliphatic/aromatic amine
Dialkylarylamine
Aminopyrimidine
Aralkylamine
Benzenoid
Pyrimidine
Pyrazine
Monocyclic benzene moiety
Dicarboxylic acid or derivatives
Heteroaromatic compound
Tertiary amine
Secondary carboxylic acid amide
Carboxamide group
Amino acid
Carboxylic acid
Organoheterocyclic compound
Azacycle
Organic oxygen compound
Primary amine
Carbonyl group
Amine
Organic oxide
Organic nitrogen compound
Organopnictogen compound
Hydrocarbon derivative
Organooxygen compound
Organonitrogen compound
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

monocarboxylic acid amide (CHEBI:44185 )
dicarboxylic acid (CHEBI:44185 )
pteridines (CHEBI:44185 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

Orange-brown, crystalline powder (5).

Experimental Properties

Property	Value
Melting Point	195°C
Boiling Point	Not Available
Solubility	2600 mg/L
LogP	-1.85

Predicted Properties

Property	Value	Source
Water Solubility	0.17 g/L	ALOGPS
logP	-0.91	ALOGPS
logP	-0.24	ChemAxon
logS	-3.4	ALOGPS
pKa (Strongest Acidic)	3.26	ChemAxon
pKa (Strongest Basic)	1.8	ChemAxon
Physiological Charge	-2	ChemAxon
Hydrogen Acceptor Count	12	ChemAxon
Hydrogen Donor Count	5	ChemAxon
Polar Surface Area	210.54 Å²	ChemAxon
Rotatable Bond Count	9	ChemAxon
Refractivity	119.21 m³·mol⁻¹	ChemAxon
Polarizability	44.54 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0a4i-2224900000-2f01d2daa7d3813c673a	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positive	splash10-001i-3122290000-fa019cd3d12beee4e641	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-qTof , Positive	splash10-004i-0950000000-ca28d8dfdf780c201716	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-0a4i-1819500000-3159955c0d961d305b13	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-0a4i-0619400000-9a6d686008b68ac436ba	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-004i-2902000000-526ede2e4de609cb3d44	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 50V, Positive	splash10-004i-0900000000-cef8960392ea13368437	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-056r-0902000000-aab26d4a02edcef1a8c4	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Negative	splash10-0xy4-1813900000-07af6d8890331278a198	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Positive	splash10-0a4i-0209000000-fab54dfaa503a46c63b7	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-0009100000-8978b68caba7882f8318	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-0a4i-0309000000-6f0d42ae8490e1a1816c	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0001900000-e7bd0358d640d5e7461f	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0213900000-1fa0d7d6d64dbadf542d	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-056r-0937400000-de89bffee2deae003f47	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-056r-0921000000-3abec3045f5ab5af7a2a	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0udi-0001900000-a87855dc4c7855304f61	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0pc0-0355900000-b18b5db2a15dc639aa07	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-052f-6932000000-10efc16714372e5c2251	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0w2l-0015900000-a2d8b53f29122f89e0ff	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-03di-1414900000-98c6c8566f3e992eefea	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0udi-3932500000-6c263dd73e3456639a66	2021-09-22	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0007900000-8cba12ac60841dc8166e	2021-09-23	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a4i-1209000000-4b85d18f5dea93f16c31	2021-09-23	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-004i-1912000000-ea76f7a5ebd9b44acbea	2021-09-23	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0fai-6900000000-25b0e287457fb3845ef4	2014-09-20	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, DMSO-d6, experimental)	Not Available	2014-09-20	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100.40 MHz, DMSO-d6, experimental)	Not Available	2014-09-23	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum

Toxicity Profile

Route of Exposure

Inhalation (2); dermal (2); intravenous (2) Oral absorption is dose dependent in adults and leukemic pediatric patients. In adults, peak serum levels are reached within one to two hours. At doses of 30 mg/m^2 or less, methotrexate is generally well absorbed with a mean bioavailability of 60%. At doses greater than 80 mg/m^2, the absorption of the doses is significantly less due to a saturation effect.

Mechanism of Toxicity

Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

Metabolism

After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamate, metabolites which by hydrolysis may be converted back to methotrexate. Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase. Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors. In addition, small amounts of methotrexate polyglutamate may be converted to 7-hydroxymethotrexate; accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound. Following oral administration of methotrexate, the drug also is partially metabolized by the intestinal flora. Renal excretion is the primary route of elimination, and is dependent upon dosage and route of administration (6). Route of Elimination: Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Half Life: Low doses (less than 30 mg/m^2): 3 to 10 hours; High doses: 8 to 15 hours.

Toxicity Values

LD50: 43 mg/kg (Oral, Rat) (1)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

3, not classifiable as to its carcinogenicity to humans. (10)

Uses/Sources

Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas. Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis. Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis.

Minimum Risk Level

Not Available

Health Effects

A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis where dry cough can be an important sign. The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed Leucovorin "rescue"- as this is the folic acid based drug used) (11).

Symptoms

Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity.

Treatment

Administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first. Glucarpidase has been used intravenously in combination with thymidine and leucovorin to treat methotrexate toxicity. (7)

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

BioCyc ID

CTD ID

Stitch ID

PDB ID

ACToR ID

Not Available

Wikipedia Link

Methotrexate

References

Synthesis Reference

DrugSyn.org

MSDS

Link

General References

Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
Sessink PJ, Boer KA, Scheefhals AP, Anzion RB, Bos RP: Occupational exposure to antineoplastic agents at several departments in a hospital. Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health. 1992;64(2):105-12. [1399019 ]
Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004 Feb 28;363(9410):675-81. [15001324 ]
Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H: The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol. 2005 Feb;114(2):154-63. [15639649 ]
Maeda A, Maeda T, Imanishi Y, Golczak M, Moise AR, Palczewski K: Aberrant metabolites in mouse models of congenital blinding diseases: formation and storage of retinyl esters. Biochemistry. 2006 Apr 4;45(13):4210-9. [16566595 ]
Segura-Aguilar J: Peroxidase activity of liver microsomal vitamin D 25-hydroxylase and cytochrome P450 1A2 catalyzes 25-hydroxylation of vitamin D3 and oxidation of dopamine to aminochrome. Biochem Mol Med. 1996 Jun;58(1):122-9. [8809353 ]
Rumack BH (2009). POISINDEX(R) Information System. Englewood, CO: Micromedex, Inc. CCIS Volume 141, edition expires Aug, 2009.
Lewis RJ Sr. (ed) (1997). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: Van Nostrand Rheinhold Co.
McEvoy GK (ed) (2005). American Hospital Formulary Service - Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc.
International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Wikipedia. Methotrexate. Last Updated 31 July 2009. [Link]
Drugs.com [Link]

Gene Regulation

Up-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Down-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Targets

Target Details

1. Dihydrofolate reductase

General Function:: Nadph binding
Specific Function:: Key enzyme in folate metabolism. 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 DHFRL1.
Gene Name:: DHFR
Uniprot ID:: P00374
Molecular Weight:: 21452.61 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0 uM	Not Available	BindingDB 18050
Inhibitory	0.00000519 uM	Not Available	BindingDB 18050
Inhibitory	0.000038 uM	Not Available	BindingDB 18050
Inhibitory	0.00011 uM	Not Available	BindingDB 18050
Inhibitory	0.000179 uM	Not Available	BindingDB 18050
Inhibitory	4.42 uM	Not Available	BindingDB 18050
IC50	0.0006 uM	Not Available	BindingDB 18050
IC50	0.0007 uM	Not Available	BindingDB 18050
IC50	0.00082 uM	Not Available	BindingDB 18050
IC50	0.001 uM	Not Available	BindingDB 18050
IC50	0.0012 uM	Not Available	BindingDB 18050
IC50	0.0017 uM	Not Available	BindingDB 18050
IC50	0.002 uM	Not Available	BindingDB 18050
IC50	0.0021 uM	Not Available	BindingDB 18050
IC50	0.0027 uM	Not Available	BindingDB 18050
IC50	0.0033 uM	Not Available	BindingDB 18050
IC50	0.0038 uM	Not Available	BindingDB 18050
IC50	0.0039 uM	Not Available	BindingDB 18050
IC50	0.004 uM	Not Available	BindingDB 18050
IC50	0.0043 uM	Not Available	BindingDB 18050
IC50	0.006 uM	Not Available	BindingDB 18050
IC50	0.0079 uM	Not Available	BindingDB 18050
IC50	0.009 uM	Not Available	BindingDB 18050
IC50	0.0096 uM	Not Available	BindingDB 18050
IC50	0.0112 uM	Not Available	BindingDB 18050
IC50	0.0138 uM	Not Available	BindingDB 18050
IC50	0.0145 uM	Not Available	BindingDB 18050
IC50	0.02 uM	Not Available	BindingDB 18050
IC50	0.022 uM	Not Available	BindingDB 18050
IC50	0.024 uM	Not Available	BindingDB 18050
IC50	0.0243 uM	Not Available	BindingDB 18050
IC50	0.025 uM	Not Available	BindingDB 18050
IC50	0.026 uM	Not Available	BindingDB 18050
IC50	0.03 uM	Not Available	BindingDB 18050
IC50	0.03294 uM	Not Available	BindingDB 18050
IC50	0.035 uM	Not Available	BindingDB 18050
IC50	0.038 uM	Not Available	BindingDB 18050
IC50	0.04 uM	Not Available	BindingDB 18050
IC50	0.044 uM	Not Available	BindingDB 18050
IC50	0.066 uM	Not Available	BindingDB 18050
IC50	0.08 uM	Not Available	BindingDB 18050
IC50	0.72 uM	Not Available	BindingDB 18050

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Totani K, Matsuo I, Ihara Y, Ito Y: High-mannose-type glycan modifications of dihydrofolate reductase using glycan-methotrexate conjugates. Bioorg Med Chem. 2006 Aug 1;14(15):5220-9. Epub 2006 May 2. [16647263 ]
Uga H, Kuramori C, Ohta A, Tsuboi Y, Tanaka H, Hatakeyama M, Yamaguchi Y, Takahashi T, Kizaki M, Handa H: A new mechanism of methotrexate action revealed by target screening with affinity beads. Mol Pharmacol. 2006 Nov;70(5):1832-9. Epub 2006 Aug 25. [16936229 ]
Al-Rashood ST, Aboldahab IA, Nagi MN, Abouzeid LA, Abdel-Aziz AA, Abdel-Hamide SG, Youssef KM, Al-Obaid AM, El-Subbagh HI: Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg Med Chem. 2006 Dec 15;14(24):8608-21. Epub 2006 Sep 12. [16971132 ]
Bennett B, Langan P, Coates L, Mustyakimov M, Schoenborn B, Howell EE, Dealwis C: Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18493-8. Epub 2006 Nov 27. [17130456 ]
Assaraf YG: Molecular basis of antifolate resistance. Cancer Metastasis Rev. 2007 Mar;26(1):153-81. [17333344 ]
Hart BP, Haile WH, Licato NJ, Bolanowska WE, McGuire JJ, Coward JK: Synthesis and biological activity of folic acid and methotrexate analogues containing L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid. J Med Chem. 1996 Jan 5;39(1):56-65. [8568827 ]
Gangjee A, Devraj R, McGuire JJ, Kisliuk RL: Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines. J Med Chem. 1995 Sep 15;38(19):3798-805. [7562910 ]
Tsukamoto T, Haile WH, McGuire JJ, Coward JK: Synthesis and biological evaluation of N alpha-(4-amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithine. J Med Chem. 1996 Jun 21;39(13):2536-40. [8691451 ]
Thurmond J, Butchbach ME, Palomo M, Pease B, Rao M, Bedell L, Keyvan M, Pai G, Mishra R, Haraldsson M, Andresson T, Bragason G, Thosteinsdottir M, Bjornsson JM, Coovert DD, Burghes AH, Gurney ME, Singh J: Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy. J Med Chem. 2008 Feb 14;51(3):449-69. doi: 10.1021/jm061475p. Epub 2008 Jan 19. [18205293 ]
Nair MG, Salter DC, Kisliuk RL, Gaumont Y, North G, Sirotnak FM: Folate analogues. 21. Synthesis and antifolate and antitumor activities of N10-(cyanomethyl)-5,8-dideazafolic acid. J Med Chem. 1983 Apr;26(4):605-7. [6403710 ]
Taylor EC, Harrington PJ, Fletcher SR, Beardsley GP, Moran RG: Synthesis of the antileukemic agents 5,10-dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin. J Med Chem. 1985 Jul;28(7):914-21. [4009615 ]
Gangjee A, Namjoshi OA, Raghavan S, Queener SF, Kisliuk RL, Cody V: Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles. J Med Chem. 2013 Jun 13;56(11):4422-41. doi: 10.1021/jm400086g. Epub 2013 May 21. [23627352 ]
Graffner-Nordberg M, Marelius J, Ohlsson S, Persson A, Swedberg G, Andersson P, Andersson SE, Aqvist J, Hallberg A: Computational predictions of binding affinities to dihydrofolate reductase: synthesis and biological evaluation of methotrexate analogues. J Med Chem. 2000 Oct 19;43(21):3852-61. [11052790 ]
Cao SL, Han Y, Yuan CZ, Wang Y, Xiahou ZK, Liao J, Gao RT, Mao BB, Zhao BL, Li ZF, Xu X: Synthesis and antiproliferative activity of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline. Eur J Med Chem. 2013 Jun;64:401-9. doi: 10.1016/j.ejmech.2013.04.017. Epub 2013 Apr 15. [23665106 ]
Rosowsky A, Forsch RA, Reich VE, Freisheim JH, Moran RG: Side chain modified 5-deazafolate and 5-deazatetrahydrofolate analogues as mammalian folylpolyglutamate synthetase and glycinamide ribonucleotide formyltransferase inhibitors: synthesis and in vitro biological evaluation. J Med Chem. 1992 May 1;35(9):1578-88. [1578484 ]
Nair MG, Nanavati NT, Nair IG, Kisliuk RL, Gaumont Y, Hsiao MC, Kalman TI: Folate analogues. 26. Syntheses and antifolate activity of 10-substituted derivatives of 5,8-dideazafolic acid and of the poly-gamma-glutamyl metabolites of N10-propargyl-5,8-dideazafolic acid (PDDF). J Med Chem. 1986 Sep;29(9):1754-60. [3091832 ]
Rosowsky A, Forsch RA, Yu CS, Lazarus H, Beardsley GP: Methotrexate analogues. 21. Divergent influence of alkyl chain length on the dihydrofolate reductase affinity and cytotoxicity of methotrexate monoesters. J Med Chem. 1984 May;27(5):605-9. [6585550 ]
Hynes JB, Patil SA, Tomazic A, Kumar A, Pathak A, Tan XH, Li XQ, Ratnam M, Delcamp TJ, Freisheim JH: Inhibition of murine thymidylate synthase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin. J Med Chem. 1988 Feb;31(2):449-54. [3339615 ]
Abraham A, McGuire JJ, Galivan J, Nimec Z, Kisliuk RL, Gaumont Y, Nair MG: Folate analogues. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase. J Med Chem. 1991 Jan;34(1):222-7. [1992121 ]
Gangjee A, Devraj R, McGuire JJ, Kisliuk RL, Queener SF, Barrows LR: Classical and nonclassical furo[2,3-d]pyrimidines as novel antifolates: synthesis and biological activities. J Med Chem. 1994 Apr 15;37(8):1169-76. [8164259 ]
Hynes JB, Patil SA, Hagan RL, Cole A, Kohler W, Freisheim JH: Comparison of the biological effects of selected 5,8-dideazafolate analogues with their 2-desamino counterparts. J Med Chem. 1989 Apr;32(4):852-6. [2704031 ]
Patil SA, Shane B, Freisheim JH, Singh SK, Hynes JB: Inhibition of mammalian folylpolyglutamate synthetase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin bearing a terminal L-ornithine. J Med Chem. 1989 Jul;32(7):1559-65. [2738891 ]
Gangjee A, Yu J, McGuire JJ, Cody V, Galitsky N, Kisliuk RL, Queener SF: Design, synthesis, and X-ray crystal structure of a potent dual inhibitor of thymidylate synthase and dihydrofolate reductase as an antitumor agent. J Med Chem. 2000 Oct 19;43(21):3837-51. [11052789 ]
Nair MG, Chen SY, Kisliuk RL, Gaumont Y, Strumpf D: Folate analogues altered in the C9-N10 bridge region. 16. Synthesis and antifolate activity of 11-thiohomoaminopterin. J Med Chem. 1980 Aug;23(8):899-903. [6772788 ]
Gangjee A, Jain HD, McGuire JJ, Kisliuk RL: Benzoyl ring halogenated classical 2-amino-6-methyl-3,4-dihydro-4-oxo-5-substituted thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine antifolates as inhibitors of thymidylate synthase and as antitumor agents. J Med Chem. 2004 Dec 30;47(27):6730-9. [15615522 ]
Santos MA, Enyedy EA, Nuti E, Rossello A, Krupenko NI, Krupenko SA: Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs. Bioorg Med Chem. 2007 Feb 1;15(3):1266-74. Epub 2006 Nov 14. [17127067 ]
Rosowsky A, Bader H, Wright JE, Keyomarsi K, Matherly LH: Synthesis and biological activity of N omega-hemiphthaloyl-alpha,omega- diaminoalkanoic acid analogues of aminopterin and 3',5-dichloroaminopterin. J Med Chem. 1994 Jul 8;37(14):2167-74. [8035423 ]
Rosowsky A, Forsch RA, Freisheim JH, Moran RG: The 2-desamino and 2-desamino-2-methyl analogues of aminopterin do not inhibit dihydrofolate reductase but are potently toxic to tumor cells in culture. J Med Chem. 1989 Mar;32(3):517-20. [2918496 ]
Reynolds RC, Campbell SR, Fairchild RG, Kisliuk RL, Micca PL, Queener SF, Riordan JM, Sedwick WD, Waud WR, Leung AK, Dixon RW, Suling WJ, Borhani DW: Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation. J Med Chem. 2007 Jul 12;50(14):3283-9. Epub 2007 Jun 15. [17569517 ]
Gangjee A, Li W, Yang J, Kisliuk RL: Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. J Med Chem. 2008 Jan 10;51(1):68-76. Epub 2007 Dec 12. [18072727 ]
Gangjee A, Qiu Y, Li W, Kisliuk RL: Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates. J Med Chem. 2008 Sep 25;51(18):5789-97. doi: 10.1021/jm8006933. [18800768 ]
Gangjee A, Li W, Kisliuk RL, Cody V, Pace J, Piraino J, Makin J: 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. J Med Chem. 2009 Aug 13;52(15):4892-902. doi: 10.1021/jm900490a. [19719239 ]
Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL: Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorg Med Chem. 2012 Jul 15;20(14):4217-25. doi: 10.1016/j.bmc.2012.05.068. Epub 2012 Jun 6. [22739090 ]
Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL: Effect of C9-methyl substitution and C8-C9 conformational restriction on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines. J Med Chem. 2000 Aug 10;43(16):3125-33. [10956221 ]
Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL: Synthesis of N-[4-[1-ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid as an antifolate. J Med Chem. 2002 Apr 25;45(9):1942-8. [11960504 ]
Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL: Synthesis of classical and nonclassical, partially restricted, linear, tricyclic 5-deaza antifolates. J Med Chem. 2002 Nov 7;45(23):5173-81. [12408727 ]
Gangjee A, Yu J, Kisliuk RL, Haile WH, Sobrero G, McGuire JJ: Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents. J Med Chem. 2003 Feb 13;46(4):591-600. [12570380 ]
Gangjee A, Zeng Y, McGuire JJ, Mehraein F, Kisliuk RL: Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. J Med Chem. 2004 Dec 30;47(27):6893-901. [15615538 ]
Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL: Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. J Med Chem. 2005 Aug 11;48(16):5329-36. [16078850 ]
Gangjee A, Lin X, Kisliuk RL, McGuire JJ: Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benz oyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]be nzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents. J Med Chem. 2005 Nov 17;48(23):7215-22. [16279780 ]
Gangjee A, Zeng Y, Talreja T, McGuire JJ, Kisliuk RL, Queener SF: Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as antifolates. J Med Chem. 2007 Jun 28;50(13):3046-53. Epub 2007 Jun 7. [17552508 ]
Gangjee A, Jain HD, Queener SF, Kisliuk RL: The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents. J Med Chem. 2008 Aug 14;51(15):4589-600. doi: 10.1021/jm800244v. Epub 2008 Jul 8. [18605720 ]
Gangjee A, Jain HD, Phan J, Guo X, Queener SF, Kisliuk RL: 2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors. Bioorg Med Chem. 2010 Jan 15;18(2):953-61. doi: 10.1016/j.bmc.2009.11.029. Epub 2009 Dec 26. [20056546 ]
Gangjee A, Zaware N, Raghavan S, Ihnat M, Shenoy S, Kisliuk RL: Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents. J Med Chem. 2010 Feb 25;53(4):1563-78. doi: 10.1021/jm9011142. [20092323 ]
Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A: Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. Bioorg Med Chem. 2011 Jun 1;19(11):3585-94. doi: 10.1016/j.bmc.2011.03.067. Epub 2011 Apr 9. [21550809 ]
Rosowsky A, Forsch RA, Moran RG, Freisheim JH: Synthesis and biological activity of the 2-desamino and 2-desamino-2-methyl analogues of aminopterin and methotrexate. J Med Chem. 1991 Jan;34(1):227-34. [1992122 ]
Rosowsky A, Bader H, Freisheim JH: Synthesis and biological activity of methotrexate analogues with two acid groups and a hydrophobic aromatic ring in the side chain. J Med Chem. 1991 Feb;34(2):574-9. [1995880 ]
Barrow EW, Bourne PC, Barrow WW: Functional cloning of Bacillus anthracis dihydrofolate reductase and confirmation of natural resistance to trimethoprim. Antimicrob Agents Chemother. 2004 Dec;48(12):4643-9. [15561838 ]
Rosowsky A, Bader H, Freisheim JH: Analogues of methotrexate and aminopterin with gamma-methylene and gamma-cyano substitution of the glutamate side chain: synthesis and in vitro biological activity. J Med Chem. 1991 Jan;34(1):203-8. [1992118 ]
Piper JR, Montgomery JA: Convenient synthesis of 10-deazaaminopterin via a pteridine ylide. J Med Chem. 1980 Mar;23(3):320-1. [7365749 ]
DeGraw JI, Christie PH, Kisliuk RL, Gaumont Y, Sirotnak FM: Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins. J Med Chem. 1990 Jan;33(1):212-5. [2296020 ]
Zhang Z, Wu J, Ran F, Guo Y, Tian R, Zhou S, Wang X, Liu Z, Zhang L, Cui J, Liu J: Novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives as dihydrofolate inhibitor: design, synthesis and antifolate activity. Eur J Med Chem. 2009 Feb;44(2):764-71. doi: 10.1016/j.ejmech.2008.04.017. Epub 2008 May 4. [18555562 ]
Gangjee A, Vasudevan A, Queener SF, Kisliuk RL: 2,4-diamino-5-deaza-6-substituted pyrido[2,3-d]pyrimidine antifolates as potent and selective nonclassical inhibitors of dihydrofolate reductases. J Med Chem. 1996 Mar 29;39(7):1438-46. [8691474 ]
Gangjee A, Vidwans A, Elzein E, McGuire JJ, Queener SF, Kisliuk RL: Synthesis, 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. [11384244 ]
Al-Omary FA, Abou-Zeid LA, Nagi MN, Habib el-SE, Abdel-Aziz AA, El-Azab AS, Abdel-Hamide SG, Al-Omar MA, Al-Obaid AM, El-Subbagh HI: Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones. Bioorg Med Chem. 2010 Apr 15;18(8):2849-63. doi: 10.1016/j.bmc.2010.03.019. Epub 2010 Mar 12. [20350811 ]
Tsukamoto T, Kitazume T, McGuire JJ, Coward JK: Synthesis and biological evaluation of DL-4,4-difluoroglutamic acid and DL-gamma,gamma-difluoromethotrexate. J Med Chem. 1996 Jan 5;39(1):66-72. [8568828 ]
Rosowsky A, Mota CE, Queener SF, Waltham M, Ercikan-Abali E, Bertino JR: 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. J Med Chem. 1995 Mar 3;38(5):745-52. [7877140 ]
Corona P, Gibellini F, Cavalli A, Saxena P, Carta A, Loriga M, Luciani R, Paglietti G, Guerrieri D, Nerini E, Gupta S, Hannaert V, Michels PA, Ferrari S, Costi PM: Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors. J Med Chem. 2012 Oct 11;55(19):8318-29. doi: 10.1021/jm300563f. Epub 2012 Sep 19. [22946585 ]
Rosowsky A, Wright JE, Vaidya CM, Bader H, Forsch RA, Mota CE, Pardo J, Chen CS, Chen YN: Synthesis and potent antifolate activity and cytotoxicity of B-ring deaza analogues of the nonpolyglutamatable dihydrofolate reductase inhibitor Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl- L-ornithine (PT523). J Med Chem. 1998 Dec 17;41(26):5310-9. [9857098 ]
Zuccotto F, Brun R, Gonzalez Pacanowska D, Ruiz Perez LM, Gilbert IH: The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg Med Chem Lett. 1999 May 17;9(10):1463-8. [10360757 ]
Corona P, Loriga M, Costi MP, Ferrari S, Paglietti G: Synthesis of N-(5,7-diamino-3-phenyl-quinoxalin-2-yl)-3,4,5-substituted anilines and N-[4[(5,7-diamino-3-phenylquinoxalin-2-yl)amino]benzoyl]-l-glutamic acid diethyl ester: evaluation of in vitro anti-cancer and anti-folate activities. Eur J Med Chem. 2008 Jan;43(1):189-203. Epub 2007 Apr 18. [17532099 ]

Target Details

2. Thymidylate synthase

General Function:: Thymidylate synthase activity
Specific Function:: Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:: TYMS
Uniprot ID:: P04818
Molecular Weight:: 35715.65 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.6 uM	Not Available	BindingDB 18050
IC50	29 uM	Not Available	BindingDB 18050
IC50	36 uM	Not Available	BindingDB 18050
IC50	40 uM	Not Available	BindingDB 18050
IC50	75 uM	Not Available	BindingDB 18050
IC50	86 uM	Not Available	BindingDB 18050
IC50	100 uM	Not Available	BindingDB 18050
IC50	120 uM	Not Available	BindingDB 18050
IC50	170 uM	Not Available	BindingDB 18050
IC50	190 uM	Not Available	BindingDB 18050
IC50	>18 uM	Not Available	BindingDB 18050

References

Gangjee A, Lin X, Kisliuk RL, McGuire JJ: Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benz oyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]be nzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents. J Med Chem. 2005 Nov 17;48(23):7215-22. [16279780 ]
Gangjee A, Jain HD, Queener SF, Kisliuk RL: The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents. J Med Chem. 2008 Aug 14;51(15):4589-600. doi: 10.1021/jm800244v. Epub 2008 Jul 8. [18605720 ]
Gangjee A, Jain HD, Phan J, Guo X, Queener SF, Kisliuk RL: 2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors. Bioorg Med Chem. 2010 Jan 15;18(2):953-61. doi: 10.1016/j.bmc.2009.11.029. Epub 2009 Dec 26. [20056546 ]
Gangjee A, Vidwans A, Elzein E, McGuire JJ, Queener SF, Kisliuk RL: Synthesis, 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. [11384244 ]
Nair MG, Chen SY, Kisliuk RL, Gaumont Y, Strumpf D: Folate analogues altered in the C9-N10 bridge region. 16. Synthesis and antifolate activity of 11-thiohomoaminopterin. J Med Chem. 1980 Aug;23(8):899-903. [6772788 ]
Piper JR, McCaleb GS, Montgomery JA, Kisliuk RL, Gaumont Y, Sirotnak FM: 10-Propargylaminopterin and alkyl homologues of methotrexate as inhibitors of folate metabolism. J Med Chem. 1982 Jul;25(7):877-80. [7108907 ]
DeGraw JI, Colwell WT, Brown VH, Sato M, Kisliuk RL, Gaumont Y, Thorndike J, Sirotnak FM: Synthesis and biological evaluation of 8-deazahomofolic acid and its tetrahydro derivative. J Med Chem. 1988 Jan;31(1):150-3. [3121855 ]
DeGraw JI, Colwell WT, Kisliuk RL, Gaumont Y, Sirotnak FM: Synthesis and antifolate properties of 5,10-methylenetetrahydro-8,10-dideazaminopterin. J Med Chem. 1986 Sep;29(9):1786-9. [3091834 ]
Nair MG, Nanavati NT, Nair IG, Kisliuk RL, Gaumont Y, Hsiao MC, Kalman TI: Folate analogues. 26. Syntheses and antifolate activity of 10-substituted derivatives of 5,8-dideazafolic acid and of the poly-gamma-glutamyl metabolites of N10-propargyl-5,8-dideazafolic acid (PDDF). J Med Chem. 1986 Sep;29(9):1754-60. [3091832 ]
Gangjee A, Devraj R, McGuire JJ, Kisliuk RL: Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines. J Med Chem. 1995 Sep 15;38(19):3798-805. [7562910 ]
Gangjee A, Devraj R, McGuire JJ, Kisliuk RL, Queener SF, Barrows LR: Classical and nonclassical furo[2,3-d]pyrimidines as novel antifolates: synthesis and biological activities. J Med Chem. 1994 Apr 15;37(8):1169-76. [8164259 ]
Taylor EC, Harrington PJ, Fletcher SR, Beardsley GP, Moran RG: Synthesis of the antileukemic agents 5,10-dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin. J Med Chem. 1985 Jul;28(7):914-21. [4009615 ]
Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A: Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. Bioorg Med Chem. 2011 Jun 1;19(11):3585-94. doi: 10.1016/j.bmc.2011.03.067. Epub 2011 Apr 9. [21550809 ]
Corona P, Gibellini F, Cavalli A, Saxena P, Carta A, Loriga M, Luciani R, Paglietti G, Guerrieri D, Nerini E, Gupta S, Hannaert V, Michels PA, Ferrari S, Costi PM: Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors. J Med Chem. 2012 Oct 11;55(19):8318-29. doi: 10.1021/jm300563f. Epub 2012 Sep 19. [22946585 ]

Target Details

3. Serum albumin

General Function:: Toxic substance binding
Specific Function:: Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:: ALB
Uniprot ID:: P02768
Molecular Weight:: 69365.94 Da

References

Bolling C, Graefe T, Lubbing C, Jankevicius F, Uktveris S, Cesas A, Meyer-Moldenhauer WH, Starkmann H, Weigel M, Burk K, Hanauske AR: Phase II study of MTX-HSA in combination with cisplatin as first line treatment in patients with advanced or metastatic transitional cell carcinoma. Invest New Drugs. 2006 Nov;24(6):521-7. [16699974 ]
Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB: Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease. Am J Med Sci. 2006 Sep;332(3):156-8. [16969149 ]
Xie WJ, Feng YP, Cao SL, Zhao YF: [Study of the interaction between methotrexate and bovine serum albumin by spectrometry]. Guang Pu Xue Yu Guang Pu Fen Xi. 2006 Oct;26(10):1876-9. [17205742 ]
Kratz F, Abu Ajaj K, Warnecke A: Anticancer carrier-linked prodrugs in clinical trials. Expert Opin Investig Drugs. 2007 Jul;16(7):1037-58. [17594188 ]
Warnecke A, Fichtner I, Sass G, Kratz F: Synthesis, cleavage profile, and antitumor efficacy of an albumin-binding prodrug of methotrexate that is cleaved by plasmin and cathepsin B. Arch Pharm (Weinheim). 2007 Aug;340(8):389-95. [17628030 ]

Target Details

4. Bifunctional purine biosynthesis protein PURH

General Function:: Protein homodimerization activity
Specific Function:: Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571).
Gene Name:: ATIC
Uniprot ID:: P31939
Molecular Weight:: 64615.255 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>20 uM	Not Available	BindingDB 18050

References

DeGraw JI, Colwell WT, Brown VH, Sato M, Kisliuk RL, Gaumont Y, Thorndike J, Sirotnak FM: Synthesis and biological evaluation of 8-deazahomofolic acid and its tetrahydro derivative. J Med Chem. 1988 Jan;31(1):150-3. [3121855 ]

Target Details

5. Folate transporter 1

General Function:: Reduced folate carrier activity
Specific Function:: Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely the folate receptor, the folate transporter, and a V-type H(+)-pump.
Gene Name:: SLC19A1
Uniprot ID:: P41440
Molecular Weight:: 64867.62 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	3.5 uM	Not Available	BindingDB 18050

References

Bavetsias V, Marriott JH, Melin C, Kimbell R, Matusiak ZS, Boyle FT, Jackman AL: Design and synthesis of Cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents(,). J Med Chem. 2000 May 18;43(10):1910-26. [10821704 ]

Target Details

6. Folylpolyglutamate synthase, mitochondrial

General Function:: Tetrahydrofolylpolyglutamate synthase activity
Specific Function:: Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstituted reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates.
Gene Name:: FPGS
Uniprot ID:: Q05932
Molecular Weight:: 64608.53 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	3.2 uM	Not Available	BindingDB 18050

References

Mao Z, Pan J, Kalman TI: Design and synthesis of histidine analogues of folic acid and methotrexate as potential folylpolyglutamate synthetase inhibitors. J Med Chem. 1996 Oct 11;39(21):4340-4. [8863812 ]

Target Details

7. Nuclear receptor coactivator 1

General Function:: Transcription coactivator activity
Specific Function:: Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.
Gene Name:: NCOA1
Uniprot ID:: Q15788
Molecular Weight:: 156755.44 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>35.879 uM	Not Available	BindingDB 18050

References

Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]

Target Details

8. Nuclear receptor coactivator 3

General Function:: Transcriptional activator activity, rna polymerase ii core promoter proximal region sequence-specific binding
Specific Function:: Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Plays a central role in creating a multisubunit coactivator complex, which probably acts via remodeling of chromatin. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ER), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Displays histone acetyltransferase activity. Also involved in the coactivation of the NF-kappa-B pathway via its interaction with the NFKB1 subunit.
Gene Name:: NCOA3
Uniprot ID:: Q9Y6Q9
Molecular Weight:: 155292.535 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>35.879 uM	Not Available	BindingDB 18050

References

Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]

Target Details

9. Protein-arginine deiminase type-4

General Function:: Protein-arginine deiminase activity
Specific Function:: Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance. Citrullinates histone H1 at 'Arg-54' (to form H1R54ci), histone H3 at 'Arg-2', 'Arg-8', 'Arg-17' and/or 'Arg-26' (to form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at 'Arg-3' (to form H4R3ci). Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1: citrullination of 'Arg-54' of histone H1 (H1R54ci) results in H1 displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci. Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.
Gene Name:: PADI4
Uniprot ID:: Q9UM07
Molecular Weight:: 74078.65 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>10000 uM	Not Available	BindingDB 18050

References

Knuckley B, Luo Y, Thompson PR: Profiling Protein Arginine Deiminase 4 (PAD4): a novel screen to identify PAD4 inhibitors. Bioorg Med Chem. 2008 Jan 15;16(2):739-45. Epub 2007 Oct 13. [17964793 ]

Target Details

10. Trifunctional purine biosynthetic protein adenosine-3

General Function:: Phosphoribosylglycinamide formyltransferase activity
Specific Function:: Not Available
Gene Name:: GART
Uniprot ID:: P22102
Molecular Weight:: 107766.295 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	>20 uM	Not Available	BindingDB 18050

References

DeGraw JI, Colwell WT, Brown VH, Sato M, Kisliuk RL, Gaumont Y, Thorndike J, Sirotnak FM: Synthesis and biological evaluation of 8-deazahomofolic acid and its tetrahydro derivative. J Med Chem. 1988 Jan;31(1):150-3. [3121855 ]

Target Details

11. Cellular tumor antigen p53

General Function:: Not Available
Specific Function:: Not Available
Gene Name:: TP53
Uniprot ID:: P04637
Molecular Weight:: 43652.79 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	0.39 uM	APR_p53Act_72h_up	Apredica

References

Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Methotrexate (T3D2486)

Structure for T3D2486: Methotrexate

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