Use of a group of fgfr inhibitors for the manufacture of a medicament for the treatment of rheumatoid arthritis

Abstract

The application relates to application of FGFR as an inhibition target in preparation of a drug for treating rheumatoid arthritis, and the application of the inhibitors Pemigatinib, Erdafitinib, Infigratinib and Sufatinib can obviously reduce the area of bone erosion by a vascular pannus cell, and the application proves that the inhibitors can be used for preparing a drug for treating rheumatoid arthritis, provides a new treatment for treating rheumatoid arthritis, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, and particularly relates to application of a group of FGFR inhibitors in preparation of a medicine for treating rheumatoid arthritis. BACKGROUND

[0002] Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology, mainly characterized by inflammatory synovitis. Its characteristics are the multiple joint, symmetrical, invasive inflammation of small joints of the hand and foot, often accompanied by extra-articular organ involvement and positive rheumatoid factor in serum, which can lead to joint deformity and loss of function. Women are more susceptible, and the incidence is 2-3 times that of men. It can occur at any age, and the high incidence age is 40-60 years old.

[0003] The protein encoded by FGFR1 gene is one of the members of fibroblast growth factor receptor (FGFR) family. Currently, four kinds of FGFRs have been identified, i.e. FGFR1, FGFR2, FGFR3 and FGFR4. FGFR1 is a transmembrane protein, which belongs to receptor tyrosine kinase. When FGF binds to the extracellular segment of FGFR1, the tyrosine kinase activity region of the intracellular segment of the receptor is first autophosphorylated, and then the trans-phosphorylation of the receptor target protein occurs, so that the signal of the ligand is transmitted to the nucleus through the protein cascade reaction. FGF / FGFR1 signal transmission is essential for normal cell growth, but when it is excessive, it can cause various diseases. High levels of FGFR1 expression are found in breast cancer, brain glioma, liver cancer cells, etc.

[0004] Disease-modifying antirheumatic drugs (DMARDs) are the first-line drugs for treating rheumatoid arthritis (RA), which greatly improve the condition of some patients and can protect the joints of patients to a certain extent. However, in clinical practice, DMARDs often cause gastrointestinal reactions, liver and kidney damage, and immunosuppression and other side effects. There is also a part of patients who are not sensitive to the treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) can relieve pain, but cannot provide substantial joint protection for RA patients. Glucocorticoids can provide rapid symptomatic and disease relief, but long-term use can easily lead to osteoporosis, gastrointestinal bleeding, and serious side effects such as femoral head necrosis.

[0005] Chinese patent CN106492223A, published on 2020.01.17, discloses the application of microRNA34a5p inhibitor in the preparation of a drug for treating rheumatoid arthritis. The present application proposes that the microRNA34a5p inhibitor can be used as a biological immunosuppressant to treat rheumatoid arthritis. The present application relates to the therapeutic value of nucleic acid interference therapy for rheumatoid arthritis, and can inhibit the excessive immune activation state in the body, providing a new way for the biological treatment of rheumatoid arthritis. Another Chinese patent CN112274642A, published on 20210129, discloses the application of CK2 inhibitor in the preparation of a drug for treating rheumatoid arthritis. The CK2 inhibitor can significantly slow down the disease score of collagen-induced arthritis (CIA) mice, reduce synovial inflammation and bone erosion, and has no obvious organ toxicity and side effects, and is suitable for preparing a drug for treating rheumatoid arthritis.

[0006] However, the application of a group of FGFR inhibitors like the present application in the preparation of a drug for treating rheumatoid arthritis has not been reported. SUMMARY

[0007] The first object of the present application is to provide an application of an inhibitor to overcome the shortcomings of the prior art.

[0008] The second object of the present application is to provide a drug for treating rheumatoid arthritis.

[0009] To achieve the first object, the technical solution adopted by the present application is: the application of FGFR inhibitor in the preparation of a drug for treating rheumatoid arthritis, wherein the FGFR inhibitor is Pemigatinib, Erdafitinib, Infigratinib and Sotorasib.

[0010] To achieve the second object, the technical solution adopted by the present application is:

[0011] A drug for treating rheumatoid arthritis, wherein the drug comprises an FGFR inhibitor, and the inhibitor is Pemigatinib, Erdafitinib, Infigratinib and Sotorasib.

[0012] The present application has the following advantages:

[0013] At present, some rheumatoid arthritis (RA) patients, especially refractory rheumatoid arthritis patients, have poor response to existing drug treatment. The inhibitor of the present application can effectively treat rheumatoid arthritis bone destruction, and provides a new way for the treatment of rheumatoid arthritis. BRIEF DESCRIPTION OF DRAWINGS

[0014] ATTACHMENT Figure 1The area of the bone pieces eroded by the pannus cells under different treatments was compared. DETAILED DESCRIPTION

[0015] The application will be further described below in connection with specific embodiments. It should be understood that these embodiments are only used to illustrate the application and not used to limit the scope of the application. Furthermore, it should be understood that after reading the content disclosed in the application, those skilled in the art can make various modifications or changes to the application, and these equivalent forms also fall within the scope defined by the appended claims.

[0016] Example 1

[0017] 1. Sample source

[0018] The sample of the present study was derived from the pannus tissue of patients with active RA undergoing knee replacement in Shanghai Guanghua Hospital of Traditional Chinese and Western Medicine from January to February 2023.

[0019] 2. Main experimental reagents

[0020]

[0021] 3. Pannus bone erosion experiment

[0022] 1) After the active pannus tissue was confirmed intraoperatively, it was sampled and placed in pre-cooled PBS, transported to the laboratory on ice, and operated in a fume hood. First, wash twice with 4℃ PBS, then cut into about 1mm3 mud;

[0023] 2) Add an appropriate amount of 4mg / ml type II collagenase solution, and digest for 60min on a 37℃ shaking table;

[0024] 3) Stop digestion by adding 10% FBSDMEM culture medium, filter through a 100μm sterile filter, centrifuge at 500g for 10min, discard the supernatant, resuspend with 1ml of 10% FBSDMEN culture medium, and count the cells;

[0025] 4) Take out the bone pieces, check them under a light microscope, and then rinse them with DMEN for 3 times. Then, gently place the bone pieces on the bottom of a 96-well plate with a cotton swab. Grouping:

[0026] Control group: Pannus cells + 10% FBSDMEM culture medium;

[0027] Pemigatinib group: Pannus cells + 10% FBSDMEM culture medium containing Pemigatinib (10nM / L);

[0028] Erdafitinib group: Pannus cells + 10% FBSDMEM culture medium containing Erdafitinib (10nM / L);

[0029] Infigratinib group: Pannus cells + Infigratinib (10 nM / L) 10% FBS DMEM medium; Sorafenib group: Pannus cells + Sorafenib (10 nM / L) 10% FBS DMEM medium; 1*10 5 cells per well, 3 replicates;

[0030] 5) After 72h incubation at 37℃, 5% CO2 incubator, remove;

[0031] 6) Take out the bone slices in the fume hood, and place them in different 5cm culture dishes, add chloroform / isopentanol (24:1) for 5min, and dry on the absorbent paper; then place the bone slices in the respective culture dishes, add twice-diluted sodium hypochlorite solution, gently shake at room temperature for 15min, and dry on the absorbent paper. Ethanol gradient dehydration: place the bone slices in 75%, 90%, 95% and 100% ethanol respectively for 3min each. Stain with 0.1% toluidine blue for 3min, and then rinse with ddH2O. After drying, place the bone slices in the center of the glass slide, add neutral gum, cover with a glass slide, dry, and take pictures under 5x magnification, 3 fields of view;

[0032] 7) Calculate the bone slice erosion area ratio by ImageJ.

[0033] 8) The experiment was performed in 3 biological replicates.

[0034] 3. Statistical analysis

[0035] GraphPad Prism (V9.4.1) software was used. Statistical comparisons were made as shown in the figure legends. The test method was One-way ANOVA test. P<0.05 indicates statistical difference.

[0036] 4. Experimental results:

[0037] The absorption area was stained with toluidine blue, and 3 random fields of view were photographed under 5x magnification by optical microscope. The erosion area was quantitatively analyzed by ImageJ software. The results showed that Pemigatinib, Erdafitinib, Infigratinib and Sorafenib all significantly reduced the area of pannus cell erosion of the bone slices compared with the control group (Control). Figure 1

[0038] The above only describes the preferred embodiments of the present application, and it should be noted that for ordinary skilled persons in the art, without departing from the method of the present application, a number of improvements and supplements can be made, which should also be considered as the protection scope of the present application.​

Claims

1. Use of pemigatinib in the manufacture of a medicament for treating bone erosion in rheumatoid arthritis, characterized in that, The structural formula of the Pemigatinib is shown as formula I;

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