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
• Indication:
  In total 1 Indication(s)
  Discovery agent [ICD-11: N.A.]; Investigative; [1]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• Target: Stress-activated protein kinase 2a (p38 alpha); MK14_HUMAN; [1]
• 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

Prostate cancer [ICD-11: 2C82]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protransforming growth factor alpha (TGFA) [1]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation

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 Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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]
• Molecule Alteration: Expression; Up-regulation

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 Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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]
• Molecule Alteration: Expression; Up-regulation

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 Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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)

Key Molecule: hsa-mir-203 [1]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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.

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.