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Compound Detail

CHEMBL34259

METHOTREXATE
💊 Approved Drug
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💊 Approved Drug
CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
ChEMBL ↗ Properties Compare Identifier

Basic Information

ChEMBL ID CHEMBL34259
Name METHOTREXATE
Phase Approved
Structure Type MOL
InChI Key FBOZXECLQNJBKD-ZDUSSCGKSA-N
Therapeutic ✓ Yes

Known Names

(r)-methotrexate ADX-2191 Amethopterin CL 14377 CL-14377 D-amethopterin D-methotrexate Ebetrex EMT-25299 Emtexate high-pot Emtexate pf Jylamvo +17 more
643
Targets
1,401
Activities
4
Assay Types
30
PK Parameters
20
Publications
29
Known Names
20
Indications
1
Mechanisms

Molecular Properties

454.4
MW (Da)
0.27
ALogP
10
HBA
5
HBD
210.5
PSA (Ų)
0.29
QED
0
Ro5 Violations
9
Rot. Bonds

Drug Information

Molecule Type Small molecule
First Approval 1953
Availability Prescription
Chirality Single Enantiomer

Routes of Administration

Oral Parenteral

Flags

Black Box Warning Natural Product
USAN Stem -trexate
USAN Year 1961

Extended Properties

Molecular Formula C20H22N8O5
MW 454.45
Aromatic Rings 3
Heavy Atoms 33
NP-Likeness -0.53

Mechanism of Action

Mechanism Action Type Target Direct Efficacy
Dihydrofolate reductase inhibitor INHIBITOR Dihydrofolate reductase ✓ ✓

Indications

Arthritis Arthritis Arthritis, Juvenile Arthritis, Psoriatic Arthritis, Rheumatoid Breast Neoplasms Breast Neoplasms Breast Neoplasms Immune System Diseases Lymphoma, Non-Hodgkin Meningeal Carcinomatosis Mycosis Fungoides Neoplasms Neoplasms Precursor Cell Lymphoblastic Leukemia-Lymphoma Precursor Cell Lymphoblastic Leukemia-Lymphoma Precursor Cell Lymphoblastic Leukemia-Lymphoma Precursor Cell Lymphoblastic Leukemia-Lymphoma Psoriasis Psoriasis

ATC Classification

L01BA01
methotrexate
Level 1: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
Level 2: ANTINEOPLASTIC AGENTS
L04AX03
methotrexate
Level 1: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
Level 2: IMMUNOSUPPRESSANTS

Drug Warnings

Black Box Warning
respiratory toxicity
Country: United States
Black Box Warning
hepatotoxicity
Country: United States
Black Box Warning
hematological toxicity
Country: United States
Black Box Warning
carcinogenicity
Country: United States
Black Box Warning
gastrointestinal toxicity
Country: United States
Black Box Warning
nephrotoxicity
Country: United States
Black Box Warning
teratogenicity
Country: United States
Black Box Warning
infectious disease
Country: United States
Black Box Warning
vascular toxicity
Country: United States
Black Box Warning
dermatological toxicity
Country: United States

Activity Summary

IC50 1,232 meas. best 11.0
EC50 89 meas. best 8.49
Ki 69 meas. best 11.0
Kd 11 meas. best 10.64

Target Activity Profile

Target Type Best pChEMBL Mean pChEMBL Best (nM) # Data
Dihydrofolate reductase
CHEMBL202
 Ki 11.0 9.4333 0.0 6
Lacticaseibacillus casei
CHEMBL613075
 IC50 11.0 8.8109 0.0 22
Dihydrofolate reductase
CHEMBL1809
 Ki 10.68 7.5933 0.0 3
Dihydrofolate reductase
CHEMBL1809
 Kd 10.64 7.8844 0.0 9
Unchecked
CHEMBL612545
 IC50 10.42 7.5415 0.0 52
Plasmodium falciparum
CHEMBL364
 IC50 10.4 8.2186 0.0 21
Dihydrofolate reductase
CHEMBL2363
 Ki 10.14 10.14 0.1 1
Bifunctional dihydrofolate reductase-thymidylate synthase
CHEMBL4614
 Ki 9.89 9.89 0.1 1
Enterococcus faecium
CHEMBL357
 IC50 9.52 7.7413 0.3 8
Unchecked
CHEMBL612545
 Ki 9.46 7.3925 0.3 4
Dihydrofolate reductase
CHEMBL202
 IC50 9.22 8.0353 0.6 80
NCI-H526
CHEMBL2366102
 IC50 9.16 9.16 0.7 1
L1210
CHEMBL386
 IC50 9.08 7.9261 0.8 41
Bifunctional dihydrofolate reductase-thymidylate synthase
CHEMBL1939
 IC50 9.05 8.065 0.9 2
Dihydrofolate reductase
CHEMBL1681620
 Ki 9.0 9.0 1.0 1
Dihydrofolate reductase
CHEMBL1926
 IC50 9.0 8.5855 1.0 11
PC-3
CHEMBL390
 IC50 9.0 7.078 1.0 5
Bifunctional dihydrofolate reductase-thymidylate synthase
CHEMBL1163130
 IC50 8.96 7.96 1.1 2
Dihydrofolate reductase
CHEMBL2902
 IC50 8.89 7.9963 1.3 30
Bifunctional dihydrofolate reductase-thymidylate synthase
CHEMBL2425
 IC50 8.85 7.2979 1.4 24
Dihydrofolate reductase
CHEMBL3243913
 IC50 8.85 8.85 1.4 1
Dihydrofolate reductase
CHEMBL1075051
 IC50 8.77 7.8133 1.7 9
Dihydrofolate reductase
CHEMBL2363
 IC50 8.7 8.552 2.0 10
NCI-H1770
CHEMBL2366171
 IC50 8.7 8.7 2.0 1
Dihydrofolate reductase
CHEMBL1809
 IC50 8.66 7.9961 2.2 18
Bifunctional dihydrofolate reductase-thymidylate synthase
CHEMBL4614
 IC50 8.64 8.64 2.3 1
DEL
CHEMBL2366186
 IC50 8.51 8.51 3.1 1
L1210
CHEMBL386
 EC50 8.49 8.49 3.2 1
Mus musculus
CHEMBL375
 IC50 8.48 7.995 3.3 2
ATN-1
CHEMBL2366277
 IC50 8.41 8.41 3.9 1
HuTu80
CHEMBL614582
 EC50 8.35 8.35 4.5 1
SK-NEP-1
CHEMBL1075580
 IC50 8.32 8.32 4.8 1
P388
CHEMBL389
 IC50 8.32 7.4475 4.8 4
A549
CHEMBL392
 IC50 8.3 7.2336 5.0 14
ML-2
CHEMBL614356
 IC50 8.3 8.3 5.0 1
CCRF S-180
CHEMBL614027
 IC50 8.27 8.135 5.4 2
SCC-7
CHEMBL614147
 IC50 8.24 8.24 5.8 1
ALL-PO
CHEMBL2366294
 IC50 8.23 8.23 5.9 1
KB
CHEMBL398
 IC50 8.22 7.7544 6.0 16
BV-173
CHEMBL2366145
 IC50 8.2 8.2 6.3 1
Dihydrofolate reductase
CHEMBL4564
 IC50 8.18 7.5445 6.6 11
HL-60
CHEMBL383
 IC50 8.16 7.7423 6.9 13
RS4-11
CHEMBL2366159
 IC50 8.15 8.15 7.0 1
SCC-25
CHEMBL614901
 IC50 8.12 7.162 7.5 5
SNU1
CHEMBL614931
 IC50 8.12 8.12 7.5 1
NKM-1
CHEMBL2366133
 IC50 8.11 8.11 7.7 1
CCRF-CEM
CHEMBL382
 EC50 8.1 7.2028 7.9 46
NON-PROTEIN TARGET
CHEMBL3879801
 IC50 8.1 6.8197 8.0 39
Dihydrofolate reductase
CHEMBL6065
 IC50 8.08 7.8667 8.2 3
143B
CHEMBL614508
 IC50 8.06 8.06 8.8 1

Pharmacokinetic Data

Parameter Value Units Species
AUC 838.0 nM l-1 hr-1 Rattus norvegicus
AUC 181.78 ng.hr.mL-1 Mus musculus
AUC 272.67 ng.hr.mL-1 Mus musculus
CL 11.0 mL.min-1.kg-1 Rattus norvegicus
CL 2.1 mL.min-1.kg-1 Homo sapiens
CL 2.1 mL.min-1.kg-1 Homo sapiens
CL 0.4 mL.min-1.kg-1 Homo sapiens
CL 1.2 mL.min-1.kg-1 Canis lupus familiaris
CL 2.1 mL.min-1.kg-1 Homo sapiens
CL 2.5 mL.min-1.kg-1 Homo sapiens
CL 8.0 mL.min-1.kg-1 Macaca
CL 12.0 mL.min-1.kg-1 Rattus norvegicus
CL 0.02023 mL.min-1.g-1 Mus musculus
CL 0.217 mL.min-1.kg-1 Canis lupus familiaris
CL 9.6 mL.min-1.kg-1 Rattus norvegicus
CL 0.048 mL.min-1.kg-1 Homo sapiens
CL 0.344 mL.min-1.kg-1 Canis lupus familiaris
CL 12.47 mL.min-1.kg-1 Rattus norvegicus
CL 1.108 mL.min-1.kg-1 Homo sapiens
CL 1.5 mL.min-1.kg-1 Rattus norvegicus
Cmax 8257.0 nM l-1 hr-1 Rattus norvegicus
Cmax 266.0 nM l-1 hr-1 Rattus norvegicus
Cmax 1000000.0 nM Homo sapiens
Cmax 100.0 nM Mus musculus
Cmax 200.0 nM Mus musculus
F 5.8 % Rattus norvegicus
F 79.0 % Homo sapiens
F 70.0 % Homo sapiens
F 70.0 % Homo sapiens
F 50.0 % Homo sapiens

Activity Data Samples

Top measurements by pChEMBL value

Target Type Rel. Value Units pChEMBL Assay PubMed
Dihydrofolate reductase Ki = 0.01 nM 11.0 Inhibition of DHFR (unknown origin) 28477572
Lacticaseibacillus casei IC50 = 0.01 nM 11.0 Antibacterial activity against chlorguanide triazine-resistant Lactobacillus cas... 137981
Dihydrofolate reductase Ki = 0.021 nM 10.68 Binding affinity against Dihydrofolate reductase of Escherichia coli 3973902
Dihydrofolate reductase Kd = 0.023 nM 10.64 Thermodynamic Dissociation Constant for compound-Phe31-dihydrofolate reductase (... 3275776
Lacticaseibacillus casei IC50 = 0.03 nM 10.52 Inhibitory activity against the growth of Lactobacillus casei (ATCC 7469) was de... 2447278
Lacticaseibacillus casei IC50 = 0.03 nM 10.52 Inhibitory activity against Lactobacillus casei ATCC 7469 3091832
Dihydrofolate reductase Ki = 0.038 nM 10.42 Inhibitory activity against Trypanosoma cruzi dihydrofolate reductase 10360757
Unchecked IC50 = 0.038 nM 10.42 Inhibition of Trypanosoma cruzi PTR1 using folic acid as substrate in presence o... 35189560
Plasmodium falciparum IC50 = 0.04 nM 10.4 Antiplasmodial activity against Plasmodium falciparum W2 after 72 hrs by SYBR gr... 19734910
Plasmodium falciparum IC50 = 0.04 nM 10.4 Antiplasmodial activity against Plasmodium falciparum D10 after 72 hrs by SYBR g... 19734910
Plasmodium falciparum IC50 = 0.04 nM 10.4 Antiplasmodial activity against Plasmodium falciparum GB4 after 72 hrs by SYBR g... 19734910
Lacticaseibacillus casei IC50 = 0.05 nM 10.3 Tested for growth inhibition of Lactobacillus casei (ATCC 7649) 3121855
Lacticaseibacillus casei IC50 = 0.06 nM 10.22 Antibacterial activity against sensitive Lactobacillus casei ATCC 7469 assessed ... 137981
Plasmodium falciparum IC50 = 0.07 nM 10.15 Antiplasmodial activity against Plasmodium falciparum HB3 after 72 hrs by SYBR g... 19734910
Plasmodium falciparum IC50 = 0.07 nM 10.15 Antiplasmodial activity against Plasmodium falciparum 3D7 after 72 hrs by SYBR g... 19734910
Dihydrofolate reductase Ki = 0.073 nM 10.14 Inhibition of rat liver DHFR by enzyme kinetics assay in presence of variable DH... 19748785
Dihydrofolate reductase Ki = 0.077 nM 10.11 Inhibition of human DHFR in presence of variable DHFA level by enzyme kinetics a... 19748785
Plasmodium falciparum IC50 = 0.09 nM 10.05 Antiplasmodial activity against Plasmodium falciparum Dd2 after 72 hrs by SYBR g... 19734910
Lacticaseibacillus casei IC50 = 0.09 nM 10.05 Inhibitory activity against the growth of Lactobacillus casei (ATCC 7469) was de... 2447278
Dihydrofolate reductase Kd = 0.096 nM 10.02 Thermodynamic Dissociation Constant for compound-Phe31-dihydrofolate reductase (... 3275776

Literature References

PubMed DOI Target Context # Activities
- 10.6019/CHEMBL3885881 Rattus norvegicus 733
- 10.1101/2024.03.28.586928 ADMET 100
2810330 10.1021/jm00131a003 Dihydrofolate reductase 61
3275776 10.1021/jm00396a019 Dihydrofolate reductase 30
6139480 10.1021/jm00366a012 Mus musculus 24
38070351 10.1016/j.bmc.2023.117539 RAW264.7 22
8340923 10.1021/jm00067a020 Mus musculus 19
22480495 10.1016/j.ejmech.2012.03.016 MONO-MAC-6 18
16472241 10.2174/1570163043334794 Hepatotoxicity 18
2447278 10.1021/jm00396a029 Lacticaseibacillus casei 18
27886545 10.1016/j.ejmech.2016.11.010 NON-PROTEIN TARGET 18
9022804 10.1021/jm9505526 Mus musculus 16
3712374 10.1021/jm00156a026 Mus musculus 16
19734910 10.1038/nchembio.215 Plasmodium falciparum 14
22194678 10.1371/journal.pcbi.1002310 Hepatotoxicity 14
15615538 10.1021/jm040123k CCRF-CEM 12
8201595 10.1021/jm00037a012 Mus musculus 12
8277497 10.1021/jm00078a004 Mus musculus 12
2810330 10.1021/jm00131a003 M21 12
6546949 10.1021/jm00371a008 Mus musculus 12

Data from ChEMBL 36 via Core Engine