Drug Information

Drug (ID: DG00214) and It's Reported Resistant Information
Name
Saracatinib
Synonyms
H8H; AZD-0530; Saracatinib, AZD-0530, AZD0530; N-(5-Chloro-1,3-benzodioxol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine
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Indication
In total 3 Indication(s)
Malignant haematopoietic neoplasm [ICD-11: 2B33]
Phase 2
[1]
Osteosarcoma [ICD-11: 2B51]
Phase 2
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Phase 2
[1]
Structure
Target Proto-oncogene c-Src (SRC) SRC_HUMAN [1]
Tyrosine-protein kinase ABL1 (ABL) ABL1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C27H32ClN5O5
IsoSMILES
CN1CCN(CC1)CCOC2=CC3=C(C(=C2)OC4CCOCC4)C(=NC=N3)NC5=C(C=CC6=C5OCO6)Cl
InChI
1S/C27H32ClN5O5/c1-32-6-8-33(9-7-32)10-13-35-19-14-21-24(23(15-19)38-18-4-11-34-12-5-18)27(30-16-29-21)31-25-20(28)2-3-22-26(25)37-17-36-22/h2-3,14-16,18H,4-13,17H2,1H3,(H,29,30,31)
InChIKey
OUKYUETWWIPKQR-UHFFFAOYSA-N
PubChem CID
10302451
TTD Drug ID
D0M0XB
DrugBank ID
DB11805
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
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Lung cancer [ICD-11: 2C25]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-106a [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
miR106a/ULk1 signaling pathway Inhibition hsa05206
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Resazurin conversion assay
Mechanism Description Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase ULK1 (ULK1) [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Lung cancer [ICD-11: 2C25.5]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
miR106a/ULk1 signaling pathway Inhibition hsa05206
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
H1299 cells Lung Homo sapiens (Human) CVCL_0060
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Resazurin conversion assay
Mechanism Description Src inhibition results in autophagy activation in NSCLC cell lines. Combining Src with autophagy inhibition results in significant cell death. Induction of ULk1 upon Scr inhibition allows for autophagy activation. Src inhibition causes induction of the ULk1 targeting microRNA-106a. Expression of the "oncogenic" miR-106a sensitizes NSCLC cells to Src inhibition.
Breast cancer [ICD-11: 2C60]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-19b-3p [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell viability Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 RT-PCR
Experiment for
Drug Resistance		 MTT assay; Transwell assay; Flow cytometry assay
Mechanism Description miR-19b-3p increases saracatinib sensitivity by inhibiting the PI3k/Akt pathway and miR-19b-3p directly bound to the 3'-UTR of PIk3CA and inhibited PIk3CA expression.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: PI3-kinase alpha (PIK3CA) [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell invasion Inhibition hsa05200
Cell viability Inhibition hsa05200
PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
BT474 cells Breast Homo sapiens (Human) CVCL_0179
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay; Transwell assay; Flow cytometry assay
Mechanism Description miR-19b-3p increases saracatinib sensitivity by inhibiting the PI3k/Akt pathway and miR-19b-3p directly bound to the 3'-UTR of PIk3CA and inhibited PIk3CA expression.
References
Ref 1 miR-19b-3p inhibits breast cancer cell proliferation and reverses saracatinib-resistance by regulating PI3K/Akt pathway. Arch Biochem Biophys. 2018 May 1;645:54-60. doi: 10.1016/j.abb.2018.03.015. Epub 2018 Mar 14.
Ref 2 MicroRNA-106a targets autophagy and enhances sensitivity of lung cancer cells to Src inhibitors. Lung Cancer. 2017 May;107:73-83. doi: 10.1016/j.lungcan.2016.06.004. Epub 2016 Jun 14.

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