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Application of carvedilol to preparation of STING agonist and chemotherapeutic sensitization drug

An agonist and drug technology, applied in the field of biomedicine, can solve problems such as carvedilol

Pending Publication Date: 2021-07-06
SHANGHAI PULMONARY HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no reports of carvedilol as a small molecule drug that can enhance the efficacy of chemotherapy drugs

Method used

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  • Application of carvedilol to preparation of STING agonist and chemotherapeutic sensitization drug
  • Application of carvedilol to preparation of STING agonist and chemotherapeutic sensitization drug
  • Application of carvedilol to preparation of STING agonist and chemotherapeutic sensitization drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] In this example, small molecules that specifically bind to STING proteins were screened out through high-throughput and further verified by docking molecular docking technology. The specific experimental methods and results are as follows:

[0031] (1) High-throughput screening of small molecules specifically bound to STING proteins

[0032] On a small-molecule microarray containing 3375 active compounds, use 0.5 mg / mL BSA solution to block the isocyanate groups on the unprinted small-molecule positions on the substrate, and use a volume of 1.5 mL and a concentration of 10 μg / mL for the target Protein STING was reacted with small molecule microarray for 1 hour. figure 2 Eleven small molecules were shown to exhibit strong binding affinity to STING, including Carvedilol (9O17, figure 2 The arrow in ), which means that Carvedilol can be combined with STING.

[0033] (2) Use docking molecular docking technology to identify whether Carvedilol can bind to STING

[0034] ...

Embodiment 2

[0036] This example verifies that Carvedilol can specifically activate the cGAS-STING pathway through STING. The specific experimental methods and results are as follows:

[0037] Stimulate mouse peritoneal macrophages with cGAMP (STING activator) at a concentration of 0.1 μg / ml, then add DMSO to the control group, and add 5 μM or 10 μM Carvedilol to the experimental group, and use qRCR technology to detect chemotaxis after 2 hours and 4 hours respectively. The expression levels of factors CXCL10 and IFN-β, the results are as follows Figure 4 .

[0038] Depend on Figure 4 It can be seen that Carvedilol can enhance the expression level of IFN-β stimulated by cGAMP, indicating that Carvedilol can specifically activate the cGAS-STING pathway through STING and up-regulate the expression of IFN-β.

Embodiment 3

[0040] This embodiment verifies that Carvedilol can enhance the antitumor effect of etoposide (Etoposide), and the specific experimental methods and results are as follows:

[0041]1. Spread mouse lung cancer cell line LLC and human lung adenocarcinoma cell A549 in 12-well plates and divide them into 4 groups: add DMSO, Carvedilol (10 μM), Etoposide (50 μM) and Carvedilol (10 μM)+ Etoposide (50μM), after 24h of treatment, the expression levels of chemokines CXCL10 and IFN-β were detected by qRCR technology, and the results showed that Carvedilol could significantly enhance the expression of IFN-β up-regulated by Etoposide (such as Figure 5 ).

[0042] 2. Inject C57 mice subcutaneously with LLC cells (1x10 6 Each / only) to build a tumor model, when the long diameter of the tumor reaches 5mm, orally administer Carvedilol and Etoposide on the tenth day or so. The administration concentration of Carvedilol is 20 mg / kg, and the administration concentration of Etoposide is 40 mg / k...

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Abstract

The invention provides application of carvedilol to preparation of a STING agonist and a chemotherapeutic sensitization drug. According to the invention, it is found that the carvedilol can specifically recognize STING and activate a cGAS-cGAMP-STING signal path, and then an anti-tumor immune response is amplified, and the lifetime of a tumor patient is prolonged. The STING agonist not only can enhance the chemotherapeutic effect and solve the problem of chemotherapy resistance, but also can reduce the chemotherapeutic side effect, and can improve the life quality of a patient while prolonging the lifetime of the tumor patient.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to the application of carvedilol in the preparation of STING agonists and chemotherapy sensitizers. Background technique [0002] Cancer is considered a leading cause of death worldwide and an important barrier to increasing life expectancy. The burden of cancer morbidity and mortality is growing rapidly worldwide. Chemotherapy, as the first-line therapy for cancer patients, has a good curative effect. However, the problem of chemotherapy resistance is a major problem. Therefore, screening chemotherapeutic drug sensitizers has long been widely valued and has become a research hotspot. Immunotherapy, an innovative approach to cancer treatment, has broadly expanded its use in recent years. The combined use of chemotherapy and immunotherapy has been found to be of great potential value in the treatment of cancer. [0003] In 2008, Stimulator of Interferon Genes (STING) was recog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/403A61K31/7048A61P35/00A61P43/00
CPCA61K31/403A61K31/7048A61P35/00A61P43/00A61K2300/00
Inventor 刘海鹏党艺方陈昶费义艳
Owner SHANGHAI PULMONARY HOSPITAL
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