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Application of protein tyrosine phosphatase SHP2 inhibitor in preparation of medicine for treating osteoarthritis (OA)

A technology for tyrosine phosphatase and osteoarthritis, applied in drug combinations, antipyretics, anti-inflammatory agents, etc.

Pending Publication Date: 2021-05-21
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There has been no report about its unique pharmacological effects in the treatment of bone diseases, especially in the treatment of osteoarthritis

Method used

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  • Application of protein tyrosine phosphatase SHP2 inhibitor in preparation of medicine for treating osteoarthritis (OA)
  • Application of protein tyrosine phosphatase SHP2 inhibitor in preparation of medicine for treating osteoarthritis (OA)
  • Application of protein tyrosine phosphatase SHP2 inhibitor in preparation of medicine for treating osteoarthritis (OA)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: SHP099 inhibits DMM surgery-induced cartilage damage in mice

[0024] Technical Methods: Medial Meniscus Imbalance (DMM) Surgically Induced Mouse Osteoarthritis Model [1] , immunohistochemical staining, immunofluorescence, safranin fast green staining

[0025] Wild C57BL / 6 male mice, aged 8-10 weeks, were raised in an SPF grade animal room at 21±2°C, free to drink and eat, and alternate day and night for 12 hours. After the mice were anesthetized with Avertin (350ul-400ul), the hair on the knee joint of the right leg of the mouse was shaved to expose the knee joint, and the medial meniscus-tibial ligament was cut off with a scalpel blade to free the medial meniscus. On the second day, the mice were randomly divided into 3 groups, normal group (Sham group), model group (DMM group), and SHP099 (10 mg / kg) group. The DMM+SHP099 group was administered intraperitoneally, once a day, 100 μl each time, and the normal group and the model group were given the same am...

Embodiment 3

[0026] Example 3: SHP099 promotes cartilage damage repair under natural aging model.

[0027] Technical methods: natural aging model, safranin fast green staining

[0028] Wild C57BL / 6 male mice were raised to 20 months old under the same growth conditions as above. Mice were randomly divided into 2 groups, PBS group and SHP099 (10mg / kg) group. After 42 days of drug treatment, the experimental animals were finally euthanized, and their right legs were taken for fixed dehydration and embedded sections, and Safranin Fast Green staining was performed to observe the cartilage damage repair, and the tibia damage was scored.

Embodiment 4

[0029] Example 4: At the cellular level, SHP099 inhibits cartilage degradation and promotes cartilage synthesis.

[0030] Technical method: chondrocyte culture in vitro, qRT-PCR

[0031] Chondrocytes from wild C57 mice born within three days were digested with trypsin for 30 minutes, and then digested with 0.2% type II collagenase for more than 2 hours. The cells were collected in batches, and DMEM / F12 containing 10% serum was added to place in cultured in a CO2 incubator. Inoculated in 24-well plates after cultured to F1 generation in vitro. Before use, dilute SHP099 with DMSO into 10mmol mother solution, dispense 50ul per tube, store at -20°C, avoid repeated freezing and thawing, and detect other genes related to cartilage catabolism. After pretreatment of cells with SHP099 for 2 hours in advance, chondrocytes were stimulated with 10ng / ml IL-1β in vitro to simulate the inflammatory response of osteoarthritis. After 12 hours, the cells were collected with Trizol to extract ...

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Abstract

The invention discloses an SHP2 allosteric inhibitor SHP099 for treating osteoarthritis (OA). Aiming at a DMM model and a natural aging induced mouse OA disease model, the SHP099 can effectively inhibit mouse knee joint cartilage defects and promote cartilage repair effects. At the cellular level, the SHP099 remarkably reduces the level of cartilage degrading enzyme under the stimulation of IL-1beta and promotes the expression of cartilage synthesis genes, so that dual regulation on cartilage synthesis and catabolism are realized. In addition, the SHP099 also has the effect of promoting cartilage cell differentiation at a concentration gradient.

Description

[0001] 1. Technical field [0002] The invention belongs to the technical field of pharmacy. [0003] 2. Background technology [0004] Osteoarthritis (OA) is the most common joint disease in middle-aged and elderly people. Its pathological features are destruction of cartilage structure, narrowing of joint space, sclerosis of subchondral bone and formation of marginal osteophytes accompanied by synovial inflammation. The main symptoms of OA in the early stage include short-term joint movement disorders such as joint pain, morning stiffness and tenderness, which will later develop into joint swelling and joint deformity, which seriously affect the quality of life of patients. According to statistics, the incidence rate among people over 60 years old is 50%, and among the 75-year-olds, the incidence rate is as high as 80%. But so far, there is no recognized effective treatment strategy that can change the disease process of osteoarthritis. The existing treatment technology main...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/497A61P19/02A61P19/08A61P29/00
CPCA61K31/497A61P19/02A61P19/08A61P29/00
Inventor 孙洋徐强刘倩倩王美晶
Owner NANJING UNIV
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