Drug Information

Drug (ID: DG00403) and It's Reported Resistant Information
Name
Letrozole
Synonyms
Femara; Femera; Letoval; Letrozol; Novartis Brand of Letrozole; CGS 20267; CGS-20267; FEM-345; Femara (TN); Letrozole [USAN:INN]; CGS 20267, Femara, Piroxicam, Letrozole; Letrozole (JAN/USP/INN); 1-[Bis-(4-cyanophenyl)methyl]-1,2,4-triazole; 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole; 4,4'-((1h-1,2,4-triazol-1-yl)methylene)dibenzonitrile; 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile; 4,4'-(1H-1,2,4-triazol-1-yl-methylene)-bis(benzonitrile); 4,4'-(1H-1,2,4-triazol-1-ylmethanediyl)dibenzonitrile; 4,4'-(1H-1,2,4-triazol-1-ylmethylene)bis-Benzonitrile Letrozole; 4,4'-(1h-1,2,4-triazol-1-ylmethylene) bis-benzonitrile; 4,4'-(1h-1,2,4-triazol-1-ylmethylene)bis-benzonitrile; 4,4'-(1h-1,2,4-triazol-1-ylmethylene)bisbenzonitrile; 4-[(4-cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile
    Click to Show/Hide
Indication
In total 1 Indication(s)
Breast cancer [ICD-11: 2C60]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[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 [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C17H11N5
IsoSMILES
C1=CC(=CC=C1C#N)C(C2=CC=C(C=C2)C#N)N3C=NC=N3
InChI
1S/C17H11N5/c18-9-13-1-5-15(6-2-13)17(22-12-20-11-21-22)16-7-3-14(10-19)4-8-16/h1-8,11-12,17H
InChIKey
HPJKCIUCZWXJDR-UHFFFAOYSA-N
PubChem CID
3902
ChEBI ID
CHEBI:6413
TTD Drug ID
D0C1WH
INTEDE ID
DR0929
DrugBank ID
DB01006
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) [2], [4]
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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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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F
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340
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G
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350
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A
A
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D
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E
L
L
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V
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360
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A
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G
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F
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D
370
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L
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L
L
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380
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E
E
C
-
A
A
W
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L
E
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I
I
390
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G
G
L
L
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V
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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
K
K
L
L
L
L
F
F
A
A
P
P
N
N
L
L
L
L
410
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L
L
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D
R
R
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N
Q
Q
G
G
K
K
C
-
V
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E
E
420
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G
G
M
M
V
V
E
E
I
I
F
F
D
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
|
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
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
I
I
T
T
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D
T
T
L
L
I
I
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H
L
L
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
H
H
Q
Q
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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
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
|
C
-
K
K
N
N
V
V
V
V
P
P
L
L
Y
S
D
D
L
L
540
|
L
L
L
L
E
E
M
M
L
L
D
D
A
A
H
H
R
R
L
L
550
|
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) [1]
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
-
D
-
L
-
G
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T
-
E
290
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N
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L
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Y
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F
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N
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A
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300
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310
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L
L
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A
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A
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320
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L
L
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D
A
A
E
E
P
P
P
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I
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L
Y
Y
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S
330
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E
E
Y
Y
D
D
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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
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S
M
M
M
M
G
G
L
L
L
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N
L
L
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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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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P
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G
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F
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D
370
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L
L
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L
L
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D
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L
380
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E
E
C
C
A
A
W
W
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L
E
E
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I
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M
M
I
I
390
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G
G
L
L
V
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W
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R
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M
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E
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P
P
400
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G
G
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F
A
A
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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
C
V
V
E
E
420
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G
G
M
M
V
V
E
E
I
I
F
F
D
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
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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
|
S
S
I
I
I
I
L
L
L
L
N
N
S
S
G
G
V
V
Y
Y
460
|
T
T
F
F
L
L
S
S
S
S
T
T
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L
K
K
S
S
L
L
470
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E
E
E
E
K
K
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D
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H
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L
480
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D
D
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K
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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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L
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T
L
L
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Q
Q
Q
500
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Q
Q
H
H
Q
Q
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
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
|
C
C
K
K
N
N
V
V
V
V
P
P
L
L
Y
Y
D
G
L
L
540
|
L
L
L
L
E
E
M
M
L
L
D
D
A
A
H
H
R
R
L
L
550
|
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		 Sanger sequencing assay; dPCR assay
Mechanism Description Acquired mutations in the estrogen-receptor gene ESR1 can be a marker of resistance to aromatase inhibitors in metastatic breast cancer.
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
-
-
V
-
D
-
L
-
G
-
T
-
E
290
|
-
N
-
L
-
Y
-
F
-
Q
-
S
-
N
-
A
-
M
-
K
300
|
-
R
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S
-
K
-
K
-
N
-
S
-
L
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A
-
L
S
S
310
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L
L
T
T
A
A
D
D
Q
Q
M
M
V
V
S
S
A
A
L
L
320
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L
L
D
D
A
A
E
E
P
P
P
P
I
I
L
L
Y
Y
S
S
330
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E
E
Y
Y
D
D
P
P
T
T
R
R
P
P
F
F
S
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
D
D
R
R
E
E
L
L
V
V
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H
M
M
I
I
N
N
360
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W
W
A
A
K
K
R
R
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V
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P
G
G
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F
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V
D
D
370
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L
L
T
T
L
L
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D
D
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Q
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V
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H
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L
L
L
380
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E
E
C
C
A
A
W
W
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L
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E
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I
L
L
M
M
I
I
390
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G
G
L
L
V
V
W
W
R
R
S
S
M
M
E
E
H
H
P
P
400
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G
G
K
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
C
V
V
E
E
420
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G
G
M
M
V
V
E
E
I
I
F
F
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D
M
M
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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
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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
K
K
S
S
L
L
470
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E
E
E
E
K
K
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D
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I
I
H
H
R
R
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480
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D
D
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K
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I
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T
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D
T
T
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L
I
I
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L
L
490
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M
M
A
A
K
K
A
A
G
G
L
L
T
T
L
L
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Q
Q
Q
500
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Q
Q
H
H
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R
R
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L
A
A
Q
Q
L
L
L
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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
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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
C
K
K
N
N
V
V
V
V
P
P
L
L
Y
Y
D
G
L
L
540
|
L
L
L
L
E
E
M
M
L
L
D
D
A
A
H
H
R
R
L
L
550
|
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		 Whole-genome sequencing assay
Mechanism Description 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) [1]
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		 Sanger sequencing assay; dPCR assay
Mechanism Description Acquired mutations in the estrogen-receptor gene ESR1 can be a marker of resistance to aromatase inhibitors in metastatic breast cancer.
Key Molecule: Estrogen receptor alpha (ESR1) [4]
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) [4]
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: Estrogen receptor alpha (ESR1) [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Molecule Alteration Missense mutation
p.L536Q
 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		 Whole-genome sequencing assay
Mechanism Description 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.
References
Ref 1 Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer. 2015 Nov 15;137(10):2513-9. doi: 10.1002/ijc.29612. Epub 2015 Jun 11.
Ref 2 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 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 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.

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