Drug Information

Drug (ID: DG00267) and It's Reported Resistant Information
Name
Methotrexate
Synonyms
Methotrexate; 1959/5/2; Rheumatrex; Amethopterin; Metatrexan; Hdmtx; Abitrexate; Mexate; Methylaminopterinum; Methotrexatum; Antifolan; Metotrexato; Methylaminopterin; MTX; (S)-2-(4-(((2,4-Diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)pentanedioic acid; Methotrexat; Amethopterine; Maxtrex; Rasuvo; L-Amethopterin; A-Methopterin; A-Methpterin; Amethopterin L-; Folex-Pfs; Methotrexat-Ebewe; N-Bismethylpteroylglutamic acid; Methotrexate, L-; Metotressato [DCIT]; Methotextrate; Mexate-Aq; [3H]methotrexate
    Click to Show/Hide
Indication
In total 5 Indication(s)
Leukaemia [ICD-11: 2A60-2B33]
Approved
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Phase 3
[1]
Vitreoretinopathy [ICD-11: 9B78]
Phase 3
[1]
Rheumatoid arthritis [ICD-11: FA20]
Phase 1
[1]
Prostate cancer [ICD-11: 2C82]
Investigative
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (8 diseases)
Acute lymphocytic leukemia [ICD-11: 2B33]
[2]
Colon cancer [ICD-11: 2B90]
[3]
Colorectal cancer [ICD-11: 2B91]
[4]
Gestational trophoblastic neoplasia [ICD-11: 2C75]
[6]
Lupus erythematosus [ICD-11: 4A40]
[8]
Osteosarcoma [ICD-11: 2B51]
[3]
Psoriasis [ICD-11: EA90]
[10]
Rheumatoid arthritis [ICD-11: FA20]
[11]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (7 diseases)
Fibrosarcoma [.]
[5]
Head and neck squamous cell carcinoma [ICD-11: 2D42]
[7]
Neuroblastoma [ICD-11: 2A00]
[9]
Brain cancer [ICD-11: 2A00]
[12]
Colon cancer [ICD-11: 2B90]
[13]
Colorectal cancer [ICD-11: 2B91]
[14]
Osteosarcoma [ICD-11: 2B51]
[15]
Target Proton-coupled folate transporter (SLC46A1) PCFT_HUMAN [1]
Solute carrier family 19 member 1 (SLC19A1) S19A1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C20H22N8O5
IsoSMILES
CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
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
InChIKey
FBOZXECLQNJBKD-ZDUSSCGKSA-N
PubChem CID
126941
ChEBI ID
CHEBI:44185
TTD Drug ID
D0SV8E
VARIDT ID
DR00082
INTEDE ID
DR1045
DrugBank ID
DB00563
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Acute lymphocytic leukemia [ICD-11: 2B33]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase KRas (KRAS) [2]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
L
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model Mouse model Mus musculus
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Flow cytometric analysis assay; MTT assay
Mechanism Description Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.
Key Molecule: GTPase KRas (KRAS) [2]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
G
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
D
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model Mouse model Mus musculus
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Flow cytometric analysis assay; MTT assay
Mechanism Description Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.
References
Ref 1 miR-29 Family Inhibits Resistance to Methotrexate and Promotes Cell Apoptosis by Targeting COL3A1 and MCL1 in Osteosarcoma. Med Sci Monit. 2018 Dec 6;24:8812-8821. doi: 10.12659/MSM.911972.
Ref 2 Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11306-11311. doi: 10.1073/pnas.1608420113. Epub 2016 Sep 21.
Ref 3 Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells. Mol Cancer. 2010 Apr 30;9:96. doi: 10.1186/1476-4598-9-96.
Ref 4 TUG1 mediates methotrexate resistance in colorectal cancer via miR-186/CPEB2 axis. Biochem Biophys Res Commun. 2017 Sep 16;491(2):552-557. doi: 10.1016/j.bbrc.2017.03.042. Epub 2017 Mar 14.
Ref 5 Cloning vectors, mutagenesis, and gene disruption (ermR) for the erythromycin-producing bacterium Aeromicrobium erythreum. Appl Environ Microbiol. 1991 Sep;57(9):2758-61. doi: 10.1128/aem.57.9.2758-2761.1991.
Ref 6 Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia .Front Oncol. 2020 Apr 28;10:557. doi: 10.3389/fonc.2020.00557. eCollection 2020. 10.3389/fonc.2020.00557
Ref 7 miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo. Oncogene. 2011 Oct 27;30(43):4386-98. doi: 10.1038/onc.2011.148. Epub 2011 May 9.
Ref 8 P-glycoprotein and drug resistance in systemic autoimmune diseases .Int J Mol Sci. 2014 Mar 20;15(3):4965-76. doi: 10.3390/ijms15034965. 10.3390/ijms15034965
Ref 9 Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-kB pathwaysMol Cancer Ther. 2012 Sep;11(9):1905-14. doi: 10.1158/1535-7163.MCT-12-0121. Epub 2012 May 31.
Ref 10 ABCB1 in dermatology: roles in skin diseases and their treatment .J Mol Med (Berl). 2021 Nov;99(11):1527-1538. doi: 10.1007/s00109-021-02105-y. Epub 2021 Aug 9. 10.1007/s00109-021-02105-y
Ref 11 Drug-resistance in rheumatoid arthritis: the role of p53 gene mutations, ABC family transporters and personal factors .Curr Opin Pharmacol. 2020 Oct;54:59-71. doi: 10.1016/j.coph.2020.08.002. Epub 2020 Sep 14. 10.1016/j.coph.2020.08.002
Ref 12 A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma .Sci Rep. 2019 Jul 16;9(1):10290. doi: 10.1038/s41598-019-46700-z. 10.1038/s41598-019-46700-z
Ref 13 Underexpression of miR-224 in methotrexate resistant human colon cancer cells. Biochem Pharmacol. 2011 Dec 1;82(11):1572-82. doi: 10.1016/j.bcp.2011.08.009. Epub 2011 Aug 16.
Ref 14 H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/Beta-catenin pathway. Exp Cell Res. 2017 Jan 15;350(2):312-317. doi: 10.1016/j.yexcr.2016.12.003. Epub 2016 Dec 2.
Ref 15 miR-146b-5p promotes invasion and metastasis contributing to chemoresistance in osteosarcoma by targeting zinc and ring finger 3. Oncol Rep. 2016 Jan;35(1):275-83. doi: 10.3892/or.2015.4393. Epub 2015 Nov 4.

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