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EGFR (epidermal growth factor receptor) kinase inhibitor and application thereof in preparation of anti-cancer drugs

A technology of pharmacy and compound, applied in the field of novel EGFR kinase inhibitor and its application in the treatment of cancer, can solve unknown problems and so on

Active Publication Date: 2020-11-10
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the role of SQSTM1 in the development of EGFR TKI resistance is still unknown

Method used

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  • EGFR (epidermal growth factor receptor) kinase inhibitor and application thereof in preparation of anti-cancer drugs
  • EGFR (epidermal growth factor receptor) kinase inhibitor and application thereof in preparation of anti-cancer drugs
  • EGFR (epidermal growth factor receptor) kinase inhibitor and application thereof in preparation of anti-cancer drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0228] With a specified concentration (such as figure 1 Indicated) gefitinib treated non-small cell lung cancer cells (NSCLC) for 24 hours (for A549 and H460 cells) or 36 hours (for HCC827 cells), and the expression of SQSTM1 was determined by Western Blot. Actin was used as an internal reference protein. Experimental results such as figure 1 shown.

[0229] With a specified concentration (such as figure 2 Shown) AZD9291 treated A549, HCC827 and H460 cells for 24 hours, and the expression of SQSTM1 was determined by Western Blot. Actin was used as an internal reference protein. Experimental results such as figure 2 shown.

[0230] Western Blot operation steps:

[0231] Cells were lysed with a lysis buffer containing 2% SDS, 0.1% bromophenol blue, 10% glycerol, 1.5% DTT (dithiothreitol), and 0.1M tris-HCl (pH 6.8). The protein concentration in cell lysates was determined by BCA method protein quantification kit. Boil-denatured lysates were separated by SDS-PAGE, tran...

Embodiment 2

[0234] A549 and H460 cells were treated with DMSO, rapamycin, and gefitinib for 7 hours, and then BafA1 (bafilomycin A1) was administered or not to the above cells, and cultured for 5 hours. LC3 and SQSTM1 expressions were detected by Western Blot (refer to the Western Blot step in Example 1). Experimental results such as image 3 shown.

[0235] Depend on image 3 The results showed that the effect of gefitinib alone was similar to that of the autophagy inhibitor Baf A1, but opposite to that of the autophagy inducer rapamycin; after the combination of rapamycin and BafA1, the protein levels of LC3-II and SQSTM1 Both significantly increased, but the combination of gefitinib and BafA1 did not show a significant enhancement effect. The above experimental results indicated that gefitinib probably blocked the autophagic degradation of SQSTM1 by inhibiting autophagy, leading to its accumulation in cells.

Embodiment 3

[0237] A549 cells were transfected with GFP-RFP-LC3 plasmid for 48 hours, and then the cells were treated with EBSS, CQ, gefitinib or AZD9291, respectively. The spots of GFP-LC3 and RFP-LC3 were detected by immunofluorescence microscopy, and the experimental results were as follows Figure 4 As shown in A.

[0238] Quantification of LC3 yellow spots / red spots (%) is expressed as mean±SD of 3 independent experiments, n=10 cells. Statistical results such as Figure 4 Shown in B, where an asterisk (*) indicates a statistical difference (Student's t-test, P<0.05).

[0239] From the results of Examples 2 and 3, it can be seen that the inhibitory effect of gefitinib and AZD9291 on autophagy is similar to that of the known autophagy inhibitors bafilomycin A1 (Baf A1) and chloroquine (CQ), although they can upregulate LC3II expression (eg image 3 shown), but it negatively regulates the process of autophagic flux in cells (such as Figure 4 shown).

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Abstract

The invention discloses an EGFR (epidermal growth factor receptor) kinase inhibitor and application thereof in preparation of anti-cancer drugs, the EGFR kinase inhibitor can effectively improve EGFRTKI acquired drug resistance caused by SQSTM1 accumulation by weakening EGFR TKI alkalinity, and the EGFR kinase inhibitor is of great significance to increase of clinical treatment income of EGFR TKI.

Description

technical field [0001] The invention relates to the field of medicine; specifically, the invention relates to a novel EGFR kinase inhibitor and its application in treating cancer. Background technique [0002] Lung cancer is the malignant tumor with the highest incidence rate and the largest number of deaths in the world, posing a serious threat to human health. However, the efficacy of traditional chemotherapy in the treatment of advanced lung cancer is very limited. Epidermal Growth Factor Receptor (Epidermal Growth Factor Receptor, EGFR, ErbB1) is a member of the receptor tyrosine kinase ErbB family. Existing research evidence shows that high expression of EGFR, gene amplification or activating mutation (L858R) commonly exists in a variety of solid tumors. EGFR overexpression or activating mutations can cause excessive activation of downstream Ras / Raf / MAPK, PI3K / Akt and other cell proliferation and survival signaling pathways. Therefore, EGFR is considered to be a key ...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D495/04C07D403/04C07D491/056C07D239/48A61K31/5377A61K31/517A61K31/519A61K31/506A61P35/00
CPCC07D239/94C07D495/04C07D403/04C07D491/056C07D239/48A61P35/00A61K31/506A61K31/517A61K31/519A61K31/5377C07D413/12C07D417/12
Inventor 金洪传冯利锋应士龙杨丽贤
Owner ZHEJIANG UNIV
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