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Application of Grp94 inhibitor in preparation of medicine for treating EGFR-driven cancer

An inhibitor and drug technology, applied in the field of medicine, can solve the problems of severe skin rash and gastrointestinal tract, adverse reactions, narrow therapeutic window, etc., and achieve the effect of excellent clinical application prospects.

Active Publication Date: 2021-11-19
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the second-generation EGFR-TKI inhibitors lack selectivity to wild-type EGFR, and have severe skin rash and gastrointestinal adverse reactions, which lead to a narrow therapeutic window and limit clinical application; while the third-generation EGFR-TKIs (based on Austrian Represented by osimertinib) is a highly selective T790M mutation small molecule inhibitor, but the latest discovery is that the C797S mutation will appear when using osimertinib

Method used

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  • Application of Grp94 inhibitor in preparation of medicine for treating EGFR-driven cancer
  • Application of Grp94 inhibitor in preparation of medicine for treating EGFR-driven cancer
  • Application of Grp94 inhibitor in preparation of medicine for treating EGFR-driven cancer

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Embodiment Construction

[0147] The raw materials, reagents, and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products. For example, vectors for overexpressing wild-type HA-FBXL2, vectors for overexpressing FBXL2 membrane site mutation C420S, vectors for overexpressing Grp94, vectors for silencing Grp94, and various cell lines can all be purchased.

[0148] The sequences of the primers or gene fragments used in the following experiments of this application are as follows:

[0149]

[0150]

[0151] Experiment 1 FBXL2 targets EGFR for polyubiquitin and proteasome-mediated degradation

[0152] 1. Experimental method

[0153] In H1299 (wild-type EGFR), PC-9 (EGFR 19del ) or H1975 (EGFR L858R / T790M ) cells stably expressing shRNAs targeting FBXL2 (shFBXL2-#1 or shFBXL2-#2, HumanshFBXL2-1 and HumanshFBXL2-2 in the nucleotide sequence table), targeting GFP, overexpressing FBXL2 plasmids, and overexpressing wi...

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Abstract

The invention provides application of a Grp94 inhibitor in preparation of a medicine for treating EGFR-driven cancer. It is found for the first time that FBXL2 can act on EGFR and can effectively inhibit EGFR so as to intervene in EGFR-driven cancers; and it is also found that Grp94 is a treatment target of EGFR-mediated related tumors, FBXL2-mediated EGFR degradation can be remarkably enhanced by inhibiting Grp94, growth of EGFR-driven non-small cell lung cancer is further inhibited, and a new choice is provided for clinical treatment of EGFR-driven cancers, especially drug-tolerant cancer.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the use of Grp94 inhibitors in the preparation of medicines for treating EGFR-driven cancers. Background technique [0002] Lung cancer is the malignant tumor with the highest morbidity and mortality worldwide. Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Non-small cell lung cancer accounts for about 85% of lung cancer. Non-small cell lung cancer has the characteristics of insidious onset, high degree of malignancy, difficulty in early detection, and easy recurrence and metastasis. As a result, the prognosis of non-small cell lung cancer is very poor, and the survival rate of patients is low and the survival period is short. [0003] The pathophysiology of non-small cell lung cancer is very complex. According to the location of the disease, it can be divided into lung adenocarcinoma, lung squamous cell carcinoma, and lar...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/4196A61K31/353A61K31/517A61K31/5377A61K31/506A61P35/00G01N33/574G01N33/68
CPCA61K45/06A61K31/4196A61K31/353A61K31/517A61K31/5377A61K31/506A61P35/00G01N33/57484G01N33/57423G01N33/6893G01N2333/47A61K2300/00
Inventor 肖智雄牛孟孟
Owner SICHUAN UNIV