Drug Information

Drug (ID: DG00095) and It's Reported Resistant Information
Name
Tamoxifen
Synonyms
Tamoxifen; 10540-29-1; trans-Tamoxifen; Crisafeno; Soltamox; Tamoxifene; Diemon; Tamoxifenum; Tamoxifeno; Tamizam; Istubol; Tamoxen; Citofen; Oncomox; Valodex; Retaxim; Tamoxifene [INN-French]; Tamoxifenum [INN-Latin]; Tamoxifeno [INN-Spanish]; Tamoxifen (Z); Tamoxifen and its salts; Tamoxifen [INN:BAN]; ICI-46474; ICI 47699; TRANS FORM OF TAMOXIFEN; CCRIS 3275; UNII-094ZI81Y45; HSDB 6782; CHEMBL83; EINECS 234-118-0; 1-p-beta-Dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene; Citofen; Nourytam; Novaldex; Tamone; Tamoxifeno;Tamoxifenum; Tomaxithen; Gen-Tamoxifen; Istubal (TN); Nolvadex (TN); Nolvadex-D; Novo-Tamoxifen; Pms-Tamoxifen; Tamoplex (TN); Tamoxifen (INN); Tamoxifen (TN); Trans-Tamoxifen; Valodex (TN); TAMOXIFEN (TAMOXIFEN CITRATE (54965-24-1)); Trans-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine; (Z)-1-(p-Dimethylaminoethoxyphenyl)-1,2-diphenyl-1-butene; (Z)-2-(4-(1,2-Diphenyl-1-butenyl)phenoxy)-N,N-dimethylethanamine; (Z)-2-(4-(1,2-diphenylbut-1-enyl)phenoxy)-N,N-dimethylethanamine; (Z)-2-(para-(1,2-Diphenyl-1-butenyl)phenoxy)-N,N-dimethylamine (IUPAC); (Z)-2-[4-(1,2)-DIPHENYL-1-BUTENYL)-PHENOXY]-N,N-DIMETHYLETHANAMINE; (Z)-2-[p-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine; 1-p-beta-Dimethylamino-ethoxyphenyl-trans-1,2-diphenylbut-1-ene; 1-para-beta-Dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene; 2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine; 2-{4-[(1Z)-1,2-diphenylbut-1-en-1-yl]phenoxy}-N,N-dimethylethanamine; Tamoxifen (Hormonal therapy); [3H]tamoxifen
    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 (3 diseases)
Breast cancer [ICD-11: 2C60]
[2]
Lung cancer [ICD-11: 2C25]
[3]
Ovarian cancer [ICD-11: 2C73]
[3]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Breast cancer [ICD-11: 2C60]
[2]
Target Estrogen receptor (ESR) ESR1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C26H29NO
IsoSMILES
CC/C(=C(\\C1=CC=CC=C1)/C2=CC=C(C=C2)OCCN(C)C)/C3=CC=CC=C3
InChI
1S/C26H29NO/c1-4-25(21-11-7-5-8-12-21)26(22-13-9-6-10-14-22)23-15-17-24(18-16-23)28-20-19-27(2)3/h5-18H,4,19-20H2,1-3H3/b26-25-
InChIKey
NKANXQFJJICGDU-QPLCGJKRSA-N
PubChem CID
2733526
ChEBI ID
CHEBI:41774
TTD Drug ID
D07KSG
VARIDT ID
DR00193
DrugBank ID
DB00675
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) [4], [5], [6]
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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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation PI3K signaling pathway Activation hsa04151
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; SNP Array profiling assay
Experiment for
Drug Resistance		 Tumor biopsy assay
Mechanism Description Mutations in ESR1 were detected in 4% of cancers and clustered in the ligand-binding domain. These included p.Tyr537(Cys/Asn/Ser) mutations (three patients) that have been shown to cause constitutive activation and resistance to tamoxifen therapy in breast cancer.
Key Molecule: Estrogen receptor alpha (ESR1) [5]
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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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) [4], [6], [7]
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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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		 Circulating cell-free DNA assay; Liquid biopsy assay; Droplet digital PCR assay; Next generation assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description Recent studies have also highlighted the utility of ex vivo culturing of CTCs as a method of individualized drug susceptibility testing. Using this method, the authors found that CTCs have various mutations (including the p.D538G and p.Y537S ESR1 mutations), and showed that low-dose administration of the HSP90 inhibitor STA9090 alone or in combination with raloxifene and fulvestrant has growth-inhibitory effects.
References
Ref 1 circRNA_0025202 Regulates Tamoxifen Sensitivity and Tumor Progression via Regulating the miR-182-5p/FOXO3a Axis in Breast Cancer. Mol Ther. 2019 Sep 4;27(9):1638-1652. doi: 10.1016/j.ymthe.2019.05.011. Epub 2019 May 17.
Ref 2 MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 2008 Oct 31;283(44):29897-903. doi: 10.1074/jbc.M804612200. Epub 2008 Aug 15.
Ref 3 Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene. 2013 Feb 28;32(9):1173-82. doi: 10.1038/onc.2012.128. Epub 2012 Apr 16.
Ref 4 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 5 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 6 Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem. 2015 Jul;61(7):974-82. doi: 10.1373/clinchem.2015.238717. Epub 2015 May 15.
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