Drug Information

Drug (ID: DG00204) and It's Reported Resistant Information
Name
Fulvestrant
Synonyms
Faslodex; AstraZeneca brand of fulvestrant; Fulvestrant [USAN]; Ici 182780; ZD 182780; ZM 182780; Faslodex (TN); ZD-182780; ZD-9238; ZM-182780; Faslodex(ICI 182,780); Faslodex, ICI 182780, Fulvestrant; Fulvestrant (JAN/USAN/INN); (7R,13S,17S)-13-methyl-7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol; (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol; (7R,8S,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl) nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol; (7alpha,17beta)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol; 7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)estra-1,3,5(10)-triene-3,17-diol; 7alpha-(9-((4,4,5,5,5,-Pentafluoropentyl)sulfinyl)nonyl)estra-1,3,5(10)-triene-3,17beta-diol; 7alpha-(9-((4,4,5,5,5-Pentafluoropentyl)sulfinyl)nonyl)estra-1,3,5(10)-triene-3,17beta-diol; 7alpha-[9[(4,4,5,5,5-Pentafluropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3, 17 beta diol; ICI
    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], [3], [4]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[5]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[6]
Target Estrogen receptor (ESR) ESR1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C32H47F5O3S
IsoSMILES
C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)[C@@H](CC4=C3C=CC(=C4)O)CCCCCCCCCS(=O)CCCC(C(F)(F)F)(F)F
InChI
1S/C32H47F5O3S/c1-30-17-15-26-25-12-11-24(38)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-41(40)19-9-16-31(33,34)32(35,36)37/h11-12,21-22,26-29,38-39H,2-10,13-20H2,1H3/t22-,26-,27+,28+,29-,30+,41 /m1/s1
InChIKey
VWUXBMIQPBEWFH-WCCTWKNTSA-N
PubChem CID
104741
ChEBI ID
CHEBI:31638
TTD Drug ID
D0JO7Y
INTEDE ID
DR0756
DrugBank ID
DB00947
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
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
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Estrogen receptor alpha (ESR1) [2], [3], [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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400
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410
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420
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G
G
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M
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430
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A
A
T
T
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S
S
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R
F
F
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M
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M
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N
440
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L
L
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G
E
E
E
E
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F
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C
C
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450
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S
S
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I
I
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Y
460
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T
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F
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S
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470
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480
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D
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500
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L
L
L
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L
510
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I
I
L
L
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S
H
H
I
I
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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
|
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 Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
WHIM16 cells Breast Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole-gexome sequencing assay
Mechanism Description The ESR1-Y537S hormone-binding-domain mutation is clearly a potent cause of aromatase-inhibitor resistance.
Key Molecule: Estrogen receptor alpha (ESR1) [7], [8]
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
-
-
M
-
D
-
P
-
M
-
I
-
K
300
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R
-
S
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K
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N
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S
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A
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S
310
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L
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T
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A
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D
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M
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320
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L
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Y
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330
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E
E
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Y
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D
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P
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F
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E
340
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A
A
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M
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G
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N
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350
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A
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E
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400
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Y
460
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T
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F
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470
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E
E
E
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D
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480
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510
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I
I
L
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M
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N
520
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K
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G
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M
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E
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H
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Y
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M
M
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K
530
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C
-
K
K
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V
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P
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L
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D
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540
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L
L
L
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E
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M
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A
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R
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550
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H
H
A
A
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S
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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		 Next-generation sequencing assay
Experiment for
Drug Resistance		 Overall survival assay
Mechanism Description All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings.
Key Molecule: Estrogen receptor alpha (ESR1) [3]
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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T
-
E
290
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N
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N
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A
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300
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R
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K
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N
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S
S
310
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L
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A
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D
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A
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320
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A
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E
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C
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A
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G
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M
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A
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F
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M
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N
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L
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Q
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G
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E
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E
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F
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V
C
C
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450
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S
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I
I
I
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L
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L
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G
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V
Y
Y
460
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T
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F
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L
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470
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E
E
E
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D
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D
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Q
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510
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I
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N
520
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K
K
G
G
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M
E
E
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H
L
L
Y
Y
S
S
M
M
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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
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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		 Next-generation sequencing assay
Mechanism Description In our analysis of frequently mutated oncogenes and tumor suppressors, ESR1 mutations stood out as a common and plausible event that could contribute to resistance. We found that the mutations in both Tyr537 and Asp538 strongly promoted ER signaling in absence of ligand. This was observed biochemically as increased phosphorylation on S118, increased association with AIB1, and diminished sensitivity to HSP90 inhibitors. Functionally, the mutations in vitro promoted the expression of classical ER target genes in the absence of hormone.
Key Molecule: Estrogen receptor alpha (ESR1) [7], [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
-
D
-
L
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G
-
T
-
E
290
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-
N
-
L
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Y
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F
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S
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N
-
A
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M
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K
300
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R
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K
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K
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N
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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
|
E
E
Y
Y
D
D
P
P
T
T
R
R
P
P
F
F
S
S
E
E
340
|
A
A
S
S
M
M
M
M
G
G
L
L
L
L
T
T
N
N
L
L
350
|
A
A
D
D
R
R
E
E
L
L
V
V
H
H
M
M
I
I
N
N
360
|
W
W
A
A
K
K
R
R
V
V
P
P
G
G
F
F
V
V
D
D
370
|
L
L
T
T
L
L
H
H
D
D
Q
Q
V
V
H
H
L
L
L
L
380
|
E
E
C
C
A
A
W
W
L
L
E
E
I
I
L
L
M
M
I
I
390
|
G
G
L
L
V
V
W
W
R
R
S
S
M
M
E
E
H
H
P
P
400
|
G
G
K
K
L
L
L
L
F
F
A
A
P
P
N
N
L
L
L
L
410
|
L
L
D
D
R
R
N
N
Q
Q
G
G
K
K
C
C
V
V
E
E
420
|
G
G
M
M
V
V
E
E
I
I
F
F
D
D
M
M
L
L
L
L
430
|
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
|
T
T
F
F
L
L
S
S
S
S
T
T
L
L
K
K
S
S
L
L
470
|
E
E
E
E
K
K
D
D
H
H
I
I
H
H
R
R
V
V
L
L
480
|
D
D
K
K
I
I
T
T
D
D
T
T
L
L
I
I
H
H
L
L
490
|
M
M
A
A
K
K
A
A
G
G
L
L
T
T
L
L
Q
Q
Q
Q
500
|
Q
Q
H
H
Q
Q
R
R
L
L
A
A
Q
Q
L
L
L
L
L
L
510
|
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		 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.
References
Ref 1 Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells. Cell Physiol Biochem. 2018;51(4):1518-1532. doi: 10.1159/000495643. Epub 2018 Nov 29.
Ref 2 Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013 Sep 26;4(6):1116-30. doi: 10.1016/j.celrep.2013.08.022. Epub 2013 Sep 19.
Ref 3 ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013 Dec;45(12):1439-45. doi: 10.1038/ng.2822. Epub 2013 Nov 3.
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 miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines. Biochem Biophys Res Commun. 2010 Dec 3;403(1):120-5. doi: 10.1016/j.bbrc.2010.10.130. Epub 2010 Nov 3.
Ref 6 Imlunestrant Is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1 Wild-Type and Mutant Breast Cancer. Cancer Res. 2025 Feb 17;85(4):777-790.
Ref 7 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 8 Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients. Onco Targets Ther. 2015 Nov 11;8:3323-8. doi: 10.2147/OTT.S92443. eCollection 2015.

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