Drug Information

Drug (ID: DG01910) and It's Reported Resistant Information
Name
BI-2536
Synonyms
BI2536
    Click to Show/Hide
Type(s) of Resistant Mechanism of This Drug
  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
Brain cancer [ICD-11: 2A00]
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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: Serine/threonine-protein kinase B-raf (BRAF) [1]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
 Disease Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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420
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M
M
D
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G
G
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430
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H
G
G
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E
E
D
D
R
R
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N
R
R
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440
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450
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460
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470
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480
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A
A
490
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L
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A
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500
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510
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520
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530
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540
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550
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560
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570
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580
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590
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600
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610
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620
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630
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640
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650
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660
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670
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680
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690
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700
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710
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720
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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model GBM cells Brain Homo sapiens (Human) N.A.
In Vivo Model Athymic mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Alamar blue proliferation assay
Lung cancer [ICD-11: 2C25]
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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: Serine/threonine-protein kinase PLK1 (PLK1) [2]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PLK1 regulatory signalling pathway Regulation N.A.
Cell cycle Activation hsa04110
In Vitro Model NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description The PLK1 inhibitors GSK 461364 and BI 2536 had synergistic effect with osimertinib. Compared with osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in osimertinib-resistant cells. In NSCLC patients with epidermal growth factor receptor mutations treated with osimertinib,?PLK1?mRNA levels were negatively correlated with progression free survival of patients (R= -0.62,?P<0.05), indicating that excessive activation of PLK1 in NSCLC cells may cause cell resistant to osimertinib. Further?in vitro?experiments showed that IC50?of PLK1 inhibitors BI 6727 and GSK 461364 in osimertinib-resistant cells were lower than those in sensitive ones. Compared with the mono treatment of osimertinib, PLK1 inhibitors combined with osimertinib behaved significantly stronger effect on the proliferation of osimertinib-resistant cells.
References
Ref 1 Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating CellsCancer Res. 2015 Dec 15;75(24):5355-66. doi: 10.1158/0008-5472.CAN-14-3689. Epub 2015 Nov 16.
Ref 2 The effect of PLK1 inhibitor in osimertinib resistant non-small cell lung carcinoma cells. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023 Oct 19;52(5):558-566.

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