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Application of novel epigenetic factor inhibitor 40569Z to preparation of liver cancer drugs

A technology of epigenetic factors and inhibitors, applied in the field of pharmacy

Active Publication Date: 2021-04-02
HUNAN NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the sirtuin protein family plays an important role in different cellular processes such as apoptosis, mitochondrial biogenesis, lipid metabolism, fatty acid oxidation, cell stress response and aging, among which sirt7 is in the link between chromatin remodeling complex and PolⅠ It also plays a key role, and can also deacetylate tumor genes and inhibit the process of gene transfer rate, thereby maintaining oncogenic transformation. However, in the prior art, there is no corresponding research on sirt7 as a target site for the treatment of liver cancer. Therefore, using Sirt7 is used as a target site for small molecule drug research, and highly targeted liver cancer drugs can be obtained

Method used

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  • Application of novel epigenetic factor inhibitor 40569Z to preparation of liver cancer drugs
  • Application of novel epigenetic factor inhibitor 40569Z to preparation of liver cancer drugs
  • Application of novel epigenetic factor inhibitor 40569Z to preparation of liver cancer drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The present invention takes sirt7 as an entry point, carries out homology modeling according to the molecular structure of sirt7 and its structure, and obtains such as figure 1 The virtual structure diagram of the sirt7 target site and the binding region of the target site, and a large number of small molecular compounds are used to carry out molecular docking with the structure, wherein the docking diagram of the compound 40569Z (as shown in formula I) and the sirt7 target site is as follows figure 2 As shown, compound 40569Z can be completely loaded into the pocket of sirt7 target site, and has multiple interactions, such as hydrogen bond interaction, hydrophobic interaction, polarization interaction, etc., and its molecular docking score is -9.74399, which has a strong strong Binding ability, can act as an inhibitor of SIRT7.

Embodiment 2

[0027] Inhibitory Activity of Inhibitor 40569Z on Liver Cancer Cells in Vitro

[0028] Add 10% fetal calf serum solution to DMEM medium, inoculate HEPG2 cells, at a temperature of 37°C, 5% CO 2 Conditions were cultured for one day, and the cultured HEPG2 cells were mixed with 3×10 4 The density of cells / ml was inoculated on a 96-well plate, and after 24 hours of culture, a certain concentration gradient of inhibitor 40569Z was added, and after 48 hours of continuous culture, the CCK8 assay was performed to analyze the activity of the cells. Normal liver cells were used as the control group, and the analysis was performed in the same way. , get as image 3 The cell activity graphs shown, wherein graph A is the inhibitory effect of the inhibitor 40569Z on liver cancer cells, and graph B is the inhibitory effect of the inhibitor 40569Z on normal liver cells. image 3 It can be seen that the IC of the inhibitor 40569Z on the growth inhibition of liver cancer cells 50 Value = 12...

Embodiment 3

[0031] Inhibitory activity of inhibitor 40569Z on tumors in tumorigenic mice in vivo

[0032] Take 10 adult mice and inject 1×10 subcutaneously 6 / HEPG2 cells were raised in nude mice for 2 weeks in an SPF-grade environment to induce tumor formation, and were randomly divided into two groups. The two groups were given different drugs, one group was the inhibitor 40569Z, and the other group was Oxaplatin ( Oxaliplatin) was administered twice a week by intraperitoneal injection, and the dosage was 5 mg / kg each time. During the administration, the tumor volume was regularly measured, and the results were as follows: Figure 4 As shown, the tumor tissue was taken out two weeks after administration, and the weight of the tumor tissue was weighed, and the results are shown in Figure 5. Depend on Figure 4 It can be seen that the tumor volume of the mice administered with the inhibitor 40569Z basically remained unchanged, while the tumor volume of the mice administered with Oxaplat...

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Abstract

The invention belongs to the field of pharmacy, and particularly relates to an application of a novel epigenetic factor inhibitor 40569Z to preparation of liver cancer drugs. According to the invention, sirt7 is used as a target site for molecular docking, the inhibitor 40569Z has a strong binding effect on sirt7, and in vitro cell experiments and in vivo inhibition experiments prove that the inhibitor 40569Z has strong specificity, obviously inhibits the growth of liver cancer cells, obviously inhibits the growth of tumors in a mouse tumor model, can promote apoptosis of the liver cancer cells, cannot kill normal liver cells, and can be used as a micromolecular targeting drug for clinical targeting treatment of liver cancer.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to the application of a novel epigenetic factor inhibitor 40569Z in the preparation of liver cancer drugs. Background technique [0002] Liver cancer is one of the common malignant tumors in clinical practice. It has the characteristics of high malignancy, rapid disease progression, short survival period, and difficult to cure. The morbidity and mortality of liver cancer are on the rise at this stage. [0003] At present, the main treatment methods for liver cancer are surgery, radiotherapy and chemotherapy. Among them, chemotherapy drugs for liver cancer. In recent years, with the in-depth study of the pathogenesis of malignant tumors, there are many types of drugs for tumors, targeting different targets such as EGFR , VEGF / VEGFR, Raf / MAPK, HGF and other targets have been studied for many drugs. Among them, the sirtuin protein family plays an important role in different cellula...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4196A61P35/00
CPCA61K31/4196A61P35/00
Inventor 李专张晨唐文斌刘博豪肖雅丹梁诗恬李汇明
Owner HUNAN NORMAL UNIVERSITY
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