Drug Information

Drug (ID: DG00316) and It's Reported Resistant Information
Name
Tyrphostin AG-1478
Synonyms
AG-1478; 153436-53-4; Tyrphostin AG 1478; N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine; 175178-82-2; Tyrphostin AG-1478; 4-(3-Chloroanilino)-6,7-dimethoxyquinazoline; AG 1478; AG1478; TYRPHOSTIN; 4-Quinazolinamine, N-(3-chlorophenyl)-6,7-dimethoxy-; UNII-SUH0SEZ9HY; SUH0SEZ9HY; AG-1478 hydrochloride; AG-1478 (Tyrphostin AG-1478); CHEMBL7917; CHEBI:75404; N-(3-Chlorophenyl)-6,7-dimethoxy-4-quinazolinamine; NSC-693255; AK-63142; N-(3-chlorophenyl)-6,7-dimethoxy-quinazolin-4-amine; BRD6408; BRD-6408; SR-01000076156; NSC693255
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Indication
In total 1 Indication(s)
Discovery agent [ICD-11: N.A.]
Investigative
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Prostate cancer [ICD-11: 2C82]
[2]
Target Epidermal growth factor receptor (EGFR) EGFR_HUMAN [1]
Stress-activated protein kinase 2a (p38 alpha) MK14_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C16H14ClN3O2
IsoSMILES
COC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=CC=C3)Cl)OC
InChI
1S/C16H14ClN3O2/c1-21-14-7-12-13(8-15(14)22-2)18-9-19-16(12)20-11-5-3-4-10(17)6-11/h3-9H,1-2H3,(H,18,19,20)
InChIKey
GFNNBHLJANVSQV-UHFFFAOYSA-N
PubChem CID
2051
ChEBI ID
CHEBI:75404
TTD Drug ID
D0ZH1U
VARIDT ID
DR01471
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  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
Prostate cancer [ICD-11: 2C82]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Protransforming growth factor alpha (TGFA) [1]
Sensitive Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Prostate cancer [ICD-11: 2C82]
The Specified Disease Prostate cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 8.36E-10
Fold-change: 1.90E-01
Z-score: 6.41E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
EGFR/RAS signaling pathway Activation hsa01521
In Vitro Model DU-145 cells Prostate Homo sapiens (Human) CVCL_0105
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.
Key Molecule: Proepiregulin (EREG) [1]
Sensitive Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Prostate cancer [ICD-11: 2C82]
The Specified Disease Prostate cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 7.31E-11
Fold-change: 7.13E-01
Z-score: 6.92E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
EGFR/RAS signaling pathway Activation hsa01521
In Vitro Model DU-145 cells Prostate Homo sapiens (Human) CVCL_0105
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.
Key Molecule: Amphiregulin (AREG) [1]
Sensitive Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Prostate cancer [ICD-11: 2C82]
The Specified Disease Prostate cancer
The Studied Tissue Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.10E-17
Fold-change: 3.99E-01
Z-score: 9.35E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
EGFR/RAS signaling pathway Activation hsa01521
In Vitro Model DU-145 cells Prostate Homo sapiens (Human) CVCL_0105
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-203 [1]
Sensitive Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
EGFR/RAS signaling pathway Activation hsa01521
In Vitro Model DU-145 cells Prostate Homo sapiens (Human) CVCL_0105
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 Promega assay
Mechanism Description The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-203a [2]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model DU145 cells Prostate Homo sapiens (Human) CVCL_0105
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR; Western blot; Luciferase Assay; Immunohistochemistry assay
Experiment for
Drug Resistance		 Cell death and Proliferation Assay
Mechanism Description Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.
References
Ref 1 Loss of EGFR signaling regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance. Oncotarget. 2014 Jun 15;5(11):3770-84. doi: 10.18632/oncotarget.1994.
Ref 2 Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathwayMol Cancer Ther. 2014 May;13(5):1078-91. doi: 10.1158/1535-7163.MCT-13-0709. Epub 2014 Mar 14.

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