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STAT3 inhibitor and application in pharmaceutical industry

A technology of inhibitors and drugs, applied in the direction of antipyretics, anti-inflammatory agents, anti-tumor drugs, etc., can solve the problems of no reports and no therapeutic effect of diseases, etc., achieve small toxic and side effects, significant curative effect, anti-inflammatory and anti-cancer The effect of applying the foreground

Inactive Publication Date: 2014-11-26
INST OF ZOOLOGY CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The effect of 6-OAP on STAT3 and whether it has a therapeutic effect on diseases related to STAT3 abnormality have not been reported so far.

Method used

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  • STAT3 inhibitor and application in pharmaceutical industry
  • STAT3 inhibitor and application in pharmaceutical industry
  • STAT3 inhibitor and application in pharmaceutical industry

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Use Autodock Vina software to carry out molecular docking on the three-dimensional structure of 6-OAP and STAT3 (refer to the protein database http: / / www.rcsb.org / pdb / ), the SH2 domain of STAT3 protein is used as the receptor, and the 6-OAP and SH2 domains Arg609, ser611 and Ser613 amino acid residues can form hydrogen bonds (see figure 1 B, C, D), the STAT3 and SH2 domains are represented by topological cartoons (see figure 1 C) and electrostatic surface diagram rendering (see figure 1 A, B, D).

Embodiment 2

[0045] Treat H1975 cells with 50 μM biotin (Bio) and biotin-labeled 6-OAP (Bio-6-OAP), and lyse the cells after 6 hours. Using the principle of specific binding of avidin and biotin, streptavidin couple The linked agarose beads can precipitate the protein that binds to Bio-6-OAP (Input is the internal control of the total protein amount of STAT3 in the cell, and IP is the STAT3 protein obtained after precipitation), and it is found that Bio-6-OAP can bind to STAT3 (see figure 2 A). In order to further verify the specificity of the binding between 6-OAP and STAT3, H1975 cells were simultaneously treated with 100 μM 6-OAP and 50 μM Bio-6-OAP ("+" means adding the corresponding drug treatment, "-" means adding solvent control) , found that 6-OAP can compete with Bio-6-OAP to bind STAT3, and the amount of Bio-6-OAP bound to STAT3 was significantly reduced (see figure 2 B), indicating that the small molecule compound 6-OAP can specifically and stably bind to STAT3.

Embodiment 3

[0047] In order to further detect whether 6-OAP inhibits the activation of Jak2 / STAT3 pathway induced by the inflammatory factor IL-6, A549 cells were starved with serum-free medium first, then incubated with IL-6 (10ng / ml) for 1h, and then treated with different Concentration of 6-OAP (5-10μM) for 3h, or starvation-treated A549 cells were pretreated with 7.5μM 6-OAP for 3h, and then incubated with IL-6 (10ng / ml) for 0-30 minutes before collecting the cells . Experimental detection of the phosphorylation of STAT3 protein found that IL-6 significantly promoted the phosphorylation of STAT3, and after treatment with 6-OAP, this promotion was inhibited (see image 3 A, "+" means adding corresponding drug treatment, "-" means adding solvent control, Actin means total protein internal reference). Also treated H1975 and A549 cells with different concentrations of 6-OAP (5-10μM) for 12 hours (h), or treated H1975 and A549 cells with 7.5μM 6-OAP at different time points (3-24h), found...

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Abstract

The invention provides application of a sesquiterpene compound 6-OAP in preparation of STAT3 inhibitors and in treatment of diseases unusually relevant to STAT3, and a pharmaceutical composition for treatment of diseases unusually relevant to STAT3. The pharmaceutical composition contains 6-OAP. 6-OAP can quickly combine with STAT3, can significantly inhibit phosphorylation of STAT3 in a cell and animal tumor-bearing model and significantly inhibit the activity of STAT3 induced by inflammatory factors, and has no significant toxic and side effect on other normal tissues. With the advantages of proper dose, significant curative effect, definite action target, and low toxic and side effects, etc., the 6-OAP has wide anticancer and anti-inflammatory application prospects clinically.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a STAT3 (signal transduction and activator of transcription 3) inhibitor and its application in the treatment of diseases related to STAT3 abnormality, more specifically to a compound 6-O- which can inhibit the transcriptional activity of STAT3 Application of angelylplenolin (6-OAP, the compound of formula I described below) in the treatment of diseases related to STAT3 abnormality, including but not limited to inflammatory, autoimmune and neoplastic diseases. Background technique [0002] Inflammation is a pathological reaction process of the body to external stimuli, and is a very common and important basic pathological process. Many common diseases such as pneumonia, enteritis, nephritis, trauma infection and various infectious diseases are inflammatory diseases, mainly caused by different causes such as infection, allergy, air pollution and smoking. When the body's immune system detect...

Claims

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Application Information

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IPC IPC(8): A61K31/365A61P29/00A61P37/00A61P35/00
Inventor 周光飚程永现刘永强
Owner INST OF ZOOLOGY CHINESE ACAD OF SCI
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