Drug Information

Drug (ID: DG00397) and It's Reported Resistant Information
Name
Anastrozole
Synonyms
Anastrazole; Anastrole; Anastrozol; Arimidex; Asiolex; Astra brand of anastrozole; AstraZeneca brand of anastrozole; Zeneca brand of anastrozole; ZD 1033; ZD1033; Zeneca ZD 1033; Arimidex (TN); Arimidex (Zeneca); Arimidex, Anastrozole; ZD-1033; Anastrozole [USAN:INN:BAN]; Anastrozole (JAN/USAN/INN); Alpha,alpha,alpha',alpha'-tetramethyl-5(1H-1,2,4-triazol-1-ylmethyl)-m-benzenediacetonitrile; Alpha,alpha,alpha',alpha'-Tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-m-benzenediacetonitrile; 1,3-benzenediacetonitrile, a, a,a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl); 2,2'-(5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene)bis(2-methylpropionitrile); 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropanenitrile); 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)benzene-1,3-diyl]bis(2-methylpropanenitrile); 2-[3-(2-cyanopropan-2-yl)-5-(1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropanenitrile
    Click to Show/Hide
Indication
In total 1 Indication(s)
Breast cancer [ICD-11: 2C60]
Approved
[1], [2]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[1], [2]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[3]
Target Aromatase (CYP19A1) CP19A_HUMAN [2]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C17H19N5
IsoSMILES
CC(C)(C#N)C1=CC(=CC(=C1)CN2C=NC=N2)C(C)(C)C#N
InChI
1S/C17H19N5/c1-16(2,9-18)14-5-13(8-22-12-20-11-21-22)6-15(7-14)17(3,4)10-19/h5-7,11-12H,8H2,1-4H3
InChIKey
YBBLVLTVTVSKRW-UHFFFAOYSA-N
PubChem CID
2187
ChEBI ID
CHEBI:2704
TTD Drug ID
D0W0BF
VARIDT ID
DR00464
INTEDE ID
DR0113
DrugBank ID
DB01217
Type(s) of Resistant Mechanism of This Drug
  MRAP: Metabolic Reprogramming via Altered Pathways
  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
Breast cancer [ICD-11: 2C60]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Key Molecule: Deiodinase, iodothyronine type III, opposite strand (DIO3OS) [3]
Metabolic Type Glucose metabolism
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vivo Model Four-week-old female athymic BALB/c nude mice, with tumor cells Mice
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Tumor volume assay
Mechanism Description Mechanistically, DIO3OS interacts with polypyrimidine tract binding protein 1 (PTBP1) and stabilizes the mRNA of lactate dehydrogenase A (LDHA) by protecting the integrity of its 3'UTR, and subsequently upregulates LDHA expression and activates glycolytic metabolism in AI-resistant breast cancer cells. Our findings highlight the role of lncRNA in regulating the key enzyme of glycolytic metabolism in response to endocrine therapies and the potential of targeting DIO3OS to reverse AI resistance in ER-positive breast cancer.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Estrogen receptor alpha (ESR1) [1], [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.Y537S
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 2IOG
Mutant Type Structure Method: X-ray diffraction Resolution: 1.50  Å
PDB: 5DXE
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.7
TM score: 0.91757
Amino acid change:
Y537S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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300
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310
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L
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A
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320
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L
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D
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E
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330
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Y
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F
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340
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A
A
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G
G
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N
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350
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A
A
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D
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E
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L
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H
M
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I
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N
360
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A
K
K
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R
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G
G
F
F
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V
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D
370
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L
L
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T
L
L
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H
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D
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380
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E
E
C
-
A
A
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L
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I
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M
I
I
390
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G
G
L
L
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R
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M
E
E
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H
P
P
400
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G
G
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K
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L
L
L
F
F
A
A
P
P
N
N
L
L
L
L
410
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L
L
D
D
R
R
N
N
Q
Q
G
G
K
K
C
-
V
V
E
E
420
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G
G
M
M
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V
E
E
I
I
F
F
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D
M
M
L
L
L
L
430
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A
A
T
T
S
S
S
S
R
R
F
F
R
R
M
M
M
M
N
N
440
|
L
L
Q
Q
G
G
E
E
E
E
F
F
V
V
C
C
L
L
K
K
450
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S
S
I
I
I
I
L
L
L
L
N
N
S
S
G
G
V
V
Y
Y
460
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T
T
F
F
L
L
S
S
S
S
T
T
L
L
K
K
S
S
L
L
470
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E
E
E
E
K
K
D
D
H
H
I
I
H
H
R
R
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V
L
L
480
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D
D
K
K
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I
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T
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D
T
T
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L
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I
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H
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490
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M
M
A
A
K
K
A
A
G
G
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Q
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500
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Q
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R
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A
A
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L
L
510
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I
I
L
L
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S
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H
I
I
R
R
H
H
M
M
S
S
N
N
520
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K
K
G
G
M
M
E
E
H
H
L
L
Y
Y
S
S
M
M
K
K
530
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C
-
K
K
N
N
V
V
V
V
P
P
L
L
Y
S
D
D
L
L
540
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L
L
L
L
E
E
M
M
L
L
D
D
A
A
H
H
R
R
L
L
550
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H
H
A
A
P
P
T
T
S
S
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies.
Key Molecule: Estrogen receptor alpha (ESR1) [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.D538G
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 2IOG
Mutant Type Structure Method: X-ray diffraction Resolution: 1.90  Å
PDB: 4PXM
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.86
TM score: 0.90649
Amino acid change:
D538G
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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G
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290
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300
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310
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320
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L
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E
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330
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Y
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340
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A
A
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G
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350
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A
A
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N
360
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A
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G
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370
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380
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E
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C
A
A
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M
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390
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G
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H
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P
400
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G
G
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A
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P
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L
L
L
L
410
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L
L
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N
Q
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G
G
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C
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E
420
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G
G
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M
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V
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E
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I
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F
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D
M
M
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L
L
430
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A
A
T
T
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S
S
S
R
R
F
F
R
R
M
M
M
M
N
N
440
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L
L
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Q
G
G
E
E
E
E
F
F
V
V
C
C
L
L
K
K
450
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S
S
I
I
I
I
L
L
L
L
N
N
S
S
G
G
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V
Y
Y
460
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T
T
F
F
L
L
S
S
S
S
T
T
L
L
K
K
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S
L
L
470
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E
E
E
E
K
K
D
D
H
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H
R
R
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V
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L
480
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D
D
K
K
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I
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D
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T
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L
I
I
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H
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490
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M
M
A
A
K
K
A
A
G
G
L
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T
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Q
Q
500
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Q
Q
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H
Q
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R
R
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A
A
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Q
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L
L
L
L
L
510
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I
I
L
L
S
S
H
H
I
I
R
R
H
H
M
M
S
S
N
N
520
|
K
K
G
G
M
M
E
E
H
H
L
L
Y
Y
S
S
M
M
K
K
530
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C
C
K
K
N
N
V
V
V
V
P
P
L
L
Y
Y
D
G
L
L
540
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L
L
L
L
E
E
M
M
L
L
D
D
A
A
H
H
R
R
L
L
550
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H
H
A
A
P
P
T
T
S
S
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Key Molecule: Estrogen receptor alpha (ESR1) [4]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.D538G
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.60  Å
PDB: 2IOG
Mutant Type Structure Method: X-ray diffraction Resolution: 1.90  Å
PDB: 4PXM
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.86
TM score: 0.90649
Amino acid change:
D538G
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
V
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D
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L
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G
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E
290
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K
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K
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L
S
S
310
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L
L
T
T
A
A
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D
Q
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M
M
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V
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A
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L
320
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L
L
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D
A
A
E
E
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P
P
P
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I
L
L
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Y
S
S
330
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E
E
Y
Y
D
D
P
P
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T
R
R
P
P
F
F
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S
E
E
340
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A
A
S
S
M
M
M
M
G
G
L
L
L
L
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T
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N
L
L
350
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A
A
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D
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R
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E
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N
360
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W
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A
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K
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R
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G
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D
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D
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380
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E
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C
A
A
W
W
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L
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E
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L
M
M
I
I
390
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G
G
L
L
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V
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W
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R
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S
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M
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E
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H
P
P
400
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G
G
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K
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L
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F
A
A
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P
N
N
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L
L
L
410
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L
L
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D
R
R
N
N
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Q
G
G
K
K
C
C
V
V
E
E
420
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G
M
M
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E
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I
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D
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M
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L
430
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A
A
T
T
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S
S
S
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R
F
F
R
R
M
M
M
M
N
N
440
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L
L
Q
Q
G
G
E
E
E
E
F
F
V
V
C
C
L
L
K
K
450
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S
S
I
I
I
I
L
L
L
L
N
N
S
S
G
G
V
V
Y
Y
460
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T
T
F
F
L
L
S
S
S
S
T
T
L
L
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K
S
S
L
L
470
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E
E
E
E
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K
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D
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H
H
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R
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L
480
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D
D
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K
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I
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D
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T
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L
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I
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490
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M
M
A
A
K
K
A
A
G
G
L
L
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T
L
L
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Q
Q
Q
500
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Q
Q
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H
Q
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R
R
L
L
A
A
Q
Q
L
L
L
L
L
L
510
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I
I
L
L
S
S
H
H
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I
R
R
H
H
M
M
S
S
N
N
520
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K
K
G
G
M
M
E
E
H
H
L
L
Y
Y
S
S
M
M
K
K
530
|
C
C
K
K
N
N
V
V
V
V
P
P
L
L
Y
Y
D
G
L
L
540
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L
L
L
L
E
E
M
M
L
L
D
D
A
A
H
H
R
R
L
L
550
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H
H
A
A
P
P
T
T
S
S
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep sequencing assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description We report here on a novel mutation of ERalpha, in which an A to G substitution at position 1,613 resulted in substitution of aspartic acid at position 538 to glycine (D538G). The mutation was identified in liver metastases obtained from patients who developed endocrine resistance, but not in samples of primary tumors obtained prior to commencing endocrine treatment. Structural modeling indicates that D538G substitution creates a conformational change that disrupts the interaction between the receptor and either estrogen or tamoxifen, but mimics the conformation of the activated receptor. Studies in cell lines confirmed ligand-independent, constitutive activity of the mutated receptor. Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance.
Key Molecule: Estrogen receptor alpha (ESR1) [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.Y537N
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Key Molecule: Estrogen receptor alpha (ESR1) [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.Y537C
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Key Molecule: BQ323636.1 [5]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AR signalling pathway Regulation N.A.
In Vitro Model MCF-7 BQ cells Breast Homo sapiens (Human) N.A.
ZR-75 BQ cells Breast Homo sapiens (Human) N.A.
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Mechanistic study indicates that BQ overexpression enhances androgen receptor (AR) activity and in the presence of anastrozole, causes hyper-activation of AR signalling, which unexpectedly enhanced cell proliferation, through increased expression of?CDK2,?CDK4, and?CCNE1. BQ overexpression reverses the effect of anastrozole in ER+ve breast cancer in an AR-dependent manner, whilst co-treatment with the AR antagonist bicalutamide recovered its therapeutic effect both?in vitro?and?in vivo. Thus, for BQ-overexpressing breast cancer, targeting AR can combat anastrozole resistance.
References
Ref 1 Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013 Dec;45(12):1446-51. doi: 10.1038/ng.2823. Epub 2013 Nov 3.
Ref 2 Droplet digital polymerase chain reaction assay for screening of ESR1 mutations in 325 breast cancer specimens. Transl Res. 2015 Dec;166(6):540-553.e2. doi: 10.1016/j.trsl.2015.09.003. Epub 2015 Sep 14.
Ref 3 Long noncoding RNA DIO3OS induces glycolytic-dominant metabolic reprogramming to promote aromatase inhibitor resistance in breast cancer. Nat Commun. 2022 Nov 22;13(1):7160.
Ref 4 D538G mutation in estrogen receptor-Alpha: A novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013 Dec 1;73(23):6856-64. doi: 10.1158/0008-5472.CAN-13-1197. Epub 2013 Nov 11.
Ref 5 Overexpression of BQ323636.1 contributes to anastrozole resistance in AR+ve/ER+ve breast cancer. J Pathol. 2023 Oct;261(2):156-168.

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