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

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Problems solved by technology

The effect of 6-OAP on STAT3 and whether it has a therapeutic effect o

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

Example Embodiment

[0042] Example 1

[0043] The three-dimensional structure of 6-OAP and STAT3 (refer to the protein database http: / / www.rcsb.org / pdb / ) was molecularly docked using Autodock Vina software. The SH2 domain of STAT3 protein was used as the receptor, and the 6-OAP and SH2 domains were used. Arg609, ser611 and Ser613 amino acid residues can form hydrogen bonds (see figure 1 B, C, D), STAT3 and SH2 domains are represented by topological cartoon diagrams (see figure 1 c) and electrostatic surface map rendering (see figure 1 A, B, D).

Example Embodiment

[0044] Example 2

[0045] H1975 cells were treated with 50 μM biotin (Bio) and biotin-labeled 6-OAP (Bio-6-OAP), and the cells were lysed after 6 h. Using the principle of specific binding of avidin to biotin, streptavidin coupled The combined agarose beads can precipitate the protein that binds to Bio-6-OAP (Input is the internal control of the total intracellular STAT3 protein, 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 treated with 100 μM 6-OAP and 50 μM Bio-6-OAP at the same time (“+” means adding corresponding drug treatment, “-” means adding solvent control) , found that 6-OAP can bind STAT3 competitively with Bio-6-OAP, 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 t...

Example Embodiment

[0046] Example 3

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

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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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