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A kind of egfr kinase inhibitor and its application in preparing anticancer drugs

A drug and pharmaceutical technology, applied in the new EGFR kinase inhibitor and its application in the treatment of cancer, can solve unknown problems and other problems

Active Publication Date: 2022-07-19
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of egfr kinase inhibitor and its application in preparing anticancer drugs
  • A kind of egfr kinase inhibitor and its application in preparing anticancer drugs
  • A kind of egfr kinase inhibitor and its application in preparing anticancer drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0228] with the specified concentration (such as figure 1 Non-small cell lung cancer cells (NSCLC) were treated with gefitinib (shown) 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. The experimental results are as figure 1 shown.

[0229] with the specified concentration (such as figure 2 A549, HCC827 and H460 cells were treated with AZD9291 of (shown) for 24 h, and the expression of SQSTM1 was determined by Western Blot. Actin was used as an internal reference protein. The experimental results are as figure 2 shown.

[0230] Western Blot operation steps:

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

Embodiment 2

[0234] A549 and H460 cells were treated with DMSO, rapamycin, gefitinib for 7 hours, then BafA1 (bafilomycin A1) or no administration was administered to the above cells and cultured for 5 hours. LC3 and SQSTM1 expression were detected by Western Blot (refer to the Western Blot procedure in Example 1). The experimental results are 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 combined use of rapamycin and BafA1, the protein levels of LC3-II and SQSTM1 Both were significantly increased, while the combination of gefitinib and BafA1 did not show a significant enhancement effect. The above experimental results suggest that gefitinib may block 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 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 shown in A.

[0238] Quantification of LC3 yellow spots / red spots (%) is expressed as the mean±SD of 3 independent experiments, n=10 cells. Statistical results such as Figure 4 shown in B, where an asterisk (*) indicates 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 be up-regulated. LC3II expression (eg image 3 shown), but negatively regulates the process of autophagic flux in cells (e.g. Figure 4 shown).

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Abstract

The invention discloses an EGFR kinase inhibitor and its application in the preparation of anticancer drugs. The EGFR kinase inhibitor can effectively improve the EGFR TKI acquisition caused by the accumulation of SQSTM1 by reducing the basicity of EGFR TKI. Drug resistance is of great significance for improving the clinical treatment benefits of EGFR TKIs.

Description

technical field [0001] The present invention relates to the field of medicine; in particular, the present invention relates to a novel EGFR kinase inhibitor and its application in the treatment of cancer. Background technique [0002] Lung cancer is the malignant tumor with the highest incidence 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 ErbB family of receptor tyrosine kinases. Existing research evidence shows that EGFR overexpression, gene amplification or activating mutation (L858R) are prevalent in a variety of solid tumors. EGFR overexpression or activating mutation will cause the overactivation of downstream Ras / Raf / MAPK, PI3K / Akt and other cell proliferation and survival signaling pathways. Therefore, EGFR is conside...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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