Application of cucurbitacine in preparing TrkA kinase inhibitor medicines

A technology of cucurbitacin and its use, which is applied in the field of cucurbitacin in the preparation of TrkA kinase inhibitor drugs, and can solve the problems that cucurbitacin inhibits TrkA kinase prevention, alleviation and treatment.

Inactive Publication Date: 2016-04-27
CHENGDU MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] But at present, there is no use of cucurbitacin to inhibit TrkA kinase and prevent, alleviate and treat pathology related to TrkA kinase

Method used

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  • Application of cucurbitacine in preparing TrkA kinase inhibitor medicines
  • Application of cucurbitacine in preparing TrkA kinase inhibitor medicines
  • Application of cucurbitacine in preparing TrkA kinase inhibitor medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Inhibitory Activity of Cucurbitacin B on Tyrosine Kinase and Serine / Threonine Kinase

[0045] Cucurbitacin B was dissolved in DMSO to obtain a 10 mM stock solution, which was then diluted with DMSO to obtain a 25.5 μM solution and further diluted with assay buffer to obtain a concentration of 0.5 μM. Cucurbitacin B was tested at a concentration of 500 nM. The high-throughput assays for the inhibitory activities of tyrosine kinases and serine / threonine kinases are shown in Table 1.

[0046] Table 1 High-throughput test for the inhibitory activity of cucurbitacin B on protein kinases

[0047]

[0048]

[0049] The results show that cucurbitacin B can inhibit TrkA activity at a concentration of 500nM to only 5% residual activity (*residual activity is relative to the protein kinase activity of 100%, how much activity is left), this test directly proves that cucurbitacin B has A new target - TrkA.

Embodiment 2

[0050] Embodiment 2 The effect of the compounds of the present invention on the activity of protein kinases in cell models

[0051] PC-12 cells according to 1 x 10 7 cells / well in a flat-bottomed 6-well plate, and add cucurbitacin B, cucurbitacin E, and cucurbitacin I. After 6 hours of serum starvation culture, NGF was added with a final concentration of 50ng / ml and incubated for 10min. Collect the cells, centrifuge at 600G for 5 minutes to remove the supernatant, wash once with PBS, take the cell pellet, and add cell lysate to lyse the cells. The protein was collected for Western-blot detection. The kinases to be tested were phosphorylated TrkA490 site, TrkA674 / 675 site and phosphorylated Akt473 site.

[0052] The experimental results are as Figure 1-3 shown.

[0053] figure 1 The results show that cucurbitacin B, like the positive control TrkA phosphorylation inhibitor-GW441756, can inhibit protein kinase TrkA490 site and Akt473 site (signal transduction and transcript...

Embodiment 3

[0062] The therapeutic effect of embodiment 3 cucurbitacin B and cucurbitacin E on mouse skin psoriasis

[0063] Preparation of experimental animals:

[0064] BALB / c mice were anesthetized by intraperitoneal injection of pentobarbital sodium (80mg / kg), and their back hair was shaved to form an exposed area with a size of about 2cm×3cm. They were reared in single cages for 1 day and then treated with drugs according to groups. .

[0065] Experimental grouping and administration:

[0066] All the mice were randomly divided into a normal control group (control), a model group (model), a dexamethasone (Dex) group and an experimental group. 6 in each group. Control group (control): smear appropriate amount of Vaseline on the bare back of mice every day, and at the same time gavage with normal saline, 0.4mL / (time / d); model group (Model): smear 5% Vaseline on the bare back of mice regularly every day Mizamod cream 42mg, at the same time with normal saline gavage, 0.4mL / (time / d); ...

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Abstract

The invention provides an application of cucurbitacine or a derivative thereof in preparing TrkA kinase inhibitor medicines. The research shows that cucurbitacine can effectively inhibit TrkA kinase, can have good treatment or improvement effect on skin itch, atopic dermatitis, psoriasis and neuropathic pain, and thus a novel choice is provided for clinical medication.

Description

technical field [0001] The present invention relates to the new application of cucurbitacin or its derivatives. Background technique [0002] Cucurbitacins are a class of tetracyclic triterpenoids with bitter or sweet taste extracted from the traditional Chinese medicine melon stalk (bitter clove), and are effective ingredients for the treatment of hepatitis and liver cancer, including cucurbitacin B, cucurbitacin E, Su I et al. They have a common cucurbitacin core structure, for example, the structures of cucurbitacin B, cucurbitacin E and cucurbitacin I are as follows: [0003] [0004] In clinical practice, its preparations include cucurbitacin tablets for oral administration. Its clinical application can comprehensively improve the common symptoms and main signs of chronic hepatitis. It can be used to treat primary liver cancer, improve symptoms, eliminate liver pain, shrink tumors, prolong survival, and restore physical strength. However, the clinical application ...

Claims

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Application Information

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IPC IPC(8): A61K31/575A61P17/04A61P29/00A61P17/00A61P17/06A61P17/10A61P17/02A61P35/00A61P25/00
CPCA61K47/32A61K47/44A61K9/0014A61K9/06A61K31/575
Inventor 阳泰刘进杨玛丽肖翠曹小华邹强李丽梅李敏惠杨淑霞刘阳王衍堂莫春芬罗兴燕冷潇郭慧杰曾婷胡松
Owner CHENGDU MEDICAL COLLEGE
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