CN112274642A - Application of CK2 inhibitor in preparation of medicine for treating rheumatoid arthritis - Google Patents

Application of CK2 inhibitor in preparation of medicine for treating rheumatoid arthritis Download PDF

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CN112274642A
CN112274642A CN202011103656.8A CN202011103656A CN112274642A CN 112274642 A CN112274642 A CN 112274642A CN 202011103656 A CN202011103656 A CN 202011103656A CN 112274642 A CN112274642 A CN 112274642A
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inhibitor
rheumatoid arthritis
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叶华
胡凡磊
付冬冬
栗占国
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Peking University
Peking University Peoples Hospital
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The CK2 inhibitor can obviously slow down the disease score of collagen-induced arthritis (CIA) mice, reduce the synovial inflammation and bone erosion degree, has no obvious organ toxicity and side effect, and is suitable for preparing the rheumatoid arthritis treatment medicine.

Description

Application of CK2 inhibitor in preparation of medicine for treating rheumatoid arthritis
Technical Field
The invention relates to the technical field of rheumatoid arthritis treatment, in particular to application of a CK2 inhibitor in preparation of a medicament for treating rheumatoid arthritis.
Background
Rheumatoid Arthritis (RA) is an antigen-driven, T cell-mediated systemic autoimmune disease that can lead to severe joint deformity, one of the major disabling diseases. The prevalence rate of rheumatoid arthritis is about 1 percent all over the world, the prevalence rate of the rheumatoid arthritis in China is 0.24 to 0.4 percent, and the number of patients is about 500 ten thousand. At present, most patients cannot be controlled due to poor curative effect or serious adverse reaction. In the second national disabled people sampling survey conducted in 2006, disabling arthrosis ranks second in the 21-class etiology leading to limb disability, and 79.4% of them are disabling rheumatoid arthritis, which seriously affects the quality of life. Therefore, it is important to find a new target treatment method with good curative effect and small side effect.
The protein Kinase CK2, also known as Casein Kinase 2(Casein Kinase II), is a serine/threonine activating Kinase. It is composed of two catalytic subunits (CK2 alpha and CK2 alpha ') and two regulatory subunits (CK2 beta and CK2 beta'), which are widely existed in eukaryotes and participate in regulating various vital activities including growth, proliferation, differentiation and apoptosis of normal cells. Previous researches show that CK2 has a promoting effect in the processes of growing medulloblastoma tumors, proliferating endometrial cancer cells, castrating and resisting growth of prostate cancer cells and the like of children, and whether CK2 has an influence on the onset of rheumatoid arthritis is not researched at present.
Disclosure of Invention
The invention aims to provide a new application of a CK2 inhibitor and also provides a new medicament and a new mode for treating rheumatoid arthritis.
The specific technical scheme of the invention is as follows:
in a first aspect, the invention provides the use of a CK2 inhibitor for the manufacture of a medicament for the treatment of rheumatoid arthritis.
Further, in the above application, the CK2 inhibitor is CX-4945, CX5011, BMS-595, BMS-211, POM, Tetrabromobenzotriazole (TBB), DMAT, TMCB, TTP 22, (E) -3- (2,3,4, 5-tetrabromophenyl) acrylic acid (TBCA) or ellagic acid.
Further, in the above application, the therapeutic agent is an oral dosage form.
In a second aspect, the present invention also provides a therapeutic agent for rheumatoid arthritis, which comprises a CK2 inhibitor.
Further, in the above drugs, the CK2 inhibitor is CX-4945, CX5011, BMS-595, BMS-211, POM, Tetrabromobenzotriazole (TBB), DMAT, TMCB, TTP 22, (E) -3- (2,3,4, 5-tetrabromophenyl) acrylic acid (TBCA) or ellagic acid.
Further, the above drug is in oral dosage form, and the CK2 inhibitor is CX-4945.
CX-4945 English name Silmitastertib, molecular formula C H ClN O, structural formula is as follows:
Figure BDA0002726227990000021
CX-4945 can regulate the activity expression of CK2 and inhibit the activation of a CK2 regulated PI3K/Akt/mTOR signaling pathway. CX5011 is an analog of CX-4945 and binds to CK2 at the active site to inhibit CK2 activity (Undrected selected and structural determinants of a new class of protein kinase CK2 inhibitors in clinical chemicals for the treatment of cancer, biochemistry.2011Oct 4; 50(39):8478-88.doi: 10.1021/bis 2008382.Epub 2011Sep 7.).
BMS-211 (FW: 825.24) and BMS-595 (FW: 532.44) are potent and selective ATP-competitive CK2 inhibitors.
Tetrabromobenzotriazole (4,5,6,7-tetrabromobenzotriazole, TBB), an ATP-competitive CK2 inhibitor, formula C HBr N, structural formula as follows:
Figure BDA0002726227990000022
DMAT is a potent and specific CK2 inhibitor of the formula CHBr N, IC50The value was 130nM and the formula is as follows:
Figure BDA0002726227990000031
TMCB is a selective, ATP-competitive inhibitor of CK2, of the formula C H Br N O, of the formula:
Figure BDA0002726227990000032
TTP 22 is a potent CK2 inhibitor with IC50 and Ki values of 100nM and 40nM, respectively, and has the formula CH N O S, and the formula:
Figure BDA0002726227990000033
TBCA is a highly selective CK2 inhibitor with an IC50 of 110nM and a Ki of 77 nM. The molecular formula is C H Br O, and the structural formula is as follows:
Figure BDA0002726227990000034
ellagic acid (Ellagic acid, English name), a potent ATP-competitive inhibitor of CK2, has IC50 and Ki values of 40nM and 20nM, respectively, and a formula of CH O, the formula of which is as follows:
Figure BDA0002726227990000041
compared with the prior art, the invention has the following beneficial effects:
the CK2 inhibitor can effectively slow down the disease score of rheumatoid arthritis, reduce the synovial inflammation degree and the bone erosion degree caused by diseases, has no obvious toxicity and side effect on organs, can be used for preparing a rheumatoid arthritis treatment medicine, and provides a new way for treating the diseases. The medicine can be prepared into oral preparations, is convenient for treatment and has better patient compatibility.
Drawings
FIG. 1 shows the expression level of CK2 subunit alpha and beta proteins in peripheral blood of RA patients and normal Human (HC);
FIG. 2 is a schematic diagram of a collagen-induced arthritis (CIA) mouse treatment experiment;
FIG. 3 shows the arthritis scores of CX 4945-group and negative control (DMSO-group) CIA mice;
fig. 4 is a photograph of the degree of bone erosion in mice, with arrows indicating the erosion points, NC: unmolded mice, CIA-CX 4945: CIA mice of gavage CK2 inhibitor CX4945, CIA-DMSO: gavage DMSO in CIA mice;
FIG. 5 is a photograph showing the degree of proliferation and exudation of joints in mice, and arrows indicate the proliferation and exudation points of joints;
FIG. 6 shows the results of immunohistochemistry of different system organ tissues.
Detailed Description
The technical solutions of the present invention are explained and illustrated in detail below with reference to specific preferred embodiments so that those skilled in the art can better understand the present invention and implement the present invention.
Example 1 CK2 involvement in the pathogenesis of RA
The peripheral blood mononuclear cell extraction method comprises the following steps:
(1) collecting 8ml of peripheral blood by using an EDTA-containing anticoagulant sterile blood collection tube;
(2) equal amounts of PBS were taken to dilute peripheral blood (1: 1);
(3) separating Peripheral Blood Mononuclear Cells (PBMC) according to the specification of the human peripheral blood mononuclear cell separating medium;
(4) the expression level of CK2 subunit alpha and beta protein in PBMCs of RA patients and HC is analyzed by using a western mounting detection technology.
Peripheral blood CD4+The T lymphocyte extraction method comprises the following steps:
(1) extracting PBMC according to the peripheral blood mononuclear cell extraction step;
(2) adding PBS with the same volume for washing at 1800rpm for 5 minutes, and discarding the supernatant;
(3) add 200. mu.l PBS to resuspend;
(4) mu.l of FITC-CD4 was added+Staining the T antibody for 30 minutes in a dark place;
(5) adding PBS to wash and remove the unbound antibody lymphocytes, 1800rpm for 5 minutes, and removing the supernatant;
(6) adding PBS about 3ml to resuspend the lymphocytes;
(7) open flow machine sort CD4+T lymphocytes;
(8) collection of CDs 4+T lymphocytes at 12000rpm for 10 min, and discarding the supernatant;
(9) CD4 analysis of CK2 subunit alpha and beta protein in RA patient and HC by using western mounting detection technology+Expression levels in T cells.
As a result:
as shown in figure 1, CK2 subunit alpha and beta proteins are respectively in CD4+The expression level in T cells and PBMCs is obviously higher than that in the RA group CK2 subunit alpha and beta protein, wherein the HC group n is 15, and the RA group n is 15; p<0.05. It is suggested that CK2 may be involved in the onset of rheumatoid arthritis.
Example 2 therapeutic Effect of CK2 inhibitor on rheumatoid arthritis
Experimental animals: collagen-induced arthritis (CIA) mice;
CK2 inhibitor: CX 4945.
The method comprises the following steps:
(1) preparing 0.1mol/L acetic acid by double distilled water;
(2) 2.5mL of 0.1mol/L acetic acid was added to 10mg of bovine type II Collagen (CII), and the mixture was dissolved overnight at 4 ℃;
(3) adding an equal volume of Complete Freund's Adjuvant (CFA) to the dissolved CII and thoroughly emulsifying on ice;
(4) injecting 100 μ L (2 μ g/μ L) of CII and CFA emulsified emulsion into the root of the tail of each mouse;
(5) to 10mg of bovine type II Collagen (CII), 2.5mL of 0.1mol/L acetic acid was added and dissolved overnight at 4 ℃.
(6) Adding an equal volume of Incomplete Freund's Adjuvant (IFA) to the dissolved CII, and fully emulsifying on ice;
(7) injecting 50 μ L (2 μ g/μ L) of CII and IFA emulsified emulsion into the root of the tail of each mouse intradermally 21 days after the first immunization of the mouse; then observing the disease score of the CIA mouse;
(8) selecting CIA mice with similar arthritis scores, randomly dividing the CIA mice into two groups, and carrying out experiments;
CX4945 group: CIA mice were gavaged with CK2 inhibitor CX4945(20 μ L/20 mg/kg/mouse) 1 time daily for 21 days.
Negative control group (DMSO group): daily gavage of DMSO (20. mu.L/mouse) (as shown in FIG. 2) was continued for 21 days.
(9) The mice were observed daily for morbidity, sacrificed 21 days after the first dose, and examined for synovial inflammation, bone destruction and abnormal degree of tissue and organ.
As a result:
as shown in fig. 3, in the disease score of mouse synovium inflammation, the arthritis score of the group CX4945 CIA mice is significantly lower than that of the group DMSO, n of the group CX4945 is 5, and n of the group DMSO is 5; p < 0.05.
As shown in fig. 4, the bone erosion degree of CIA mice in CX4945 group was significantly lower than that of DMSO group in terms of bone destruction degree; NC stands for normal unmolded mice, CIA-CX4945 stands for CIA mice gavage with CK2 inhibitor CX4945, and CIA-DMSO stands for CIA mice negative control group with DMSO gavage. As can be seen from the figure, the degree of bone erosion of the mice is significantly reduced after gavage of the CK2 inhibitor CX 4945.
As shown in figure 5, joint proliferation and exudation were significantly lower in group CX4945 CIA mice than in the DMSO group in the score of mouse synovial inflammation. As can be seen from the figure, the mice had significantly reduced joint hyperplasia and exudation following gavage of the CK2 inhibitor CX 4945.
As shown in fig. 6, in terms of the degree of tissue and organ abnormality, it was revealed from the results of immunohistochemistry of different system organ tissues such as brain tissue, heart tissue, liver tissue, lung tissue and kidney tissue that the difference between the CX4945 group of mice and the DMSO group and unmolded mice was not significant (NC: unmolded mice, CX 4945: CIA mice in which CK2 inhibitor CX4945 was intragastrically perfused, DMSO: CIA mouse negative control group in which DMSO was perfused), wherein the unmodeled group n was 5, the CX4945 group n was 5, and the DMSO group n was 5; n.s. no statistical difference. The CK2 inhibitor CX4945 molecule can not cause the abnormality of main tissues and organs such as brain, lung, heart, liver, kidney and the like, and has no obvious organ toxicity and side effect.
The inventive concept is explained in detail herein using specific examples, which are given only to aid in understanding the core concepts of the invention. It should be understood that any obvious modifications, equivalents and other improvements made by those skilled in the art without departing from the spirit of the present invention are included in the scope of the present invention.

Claims (6)

  1. The application of the CK2 inhibitor in preparing a medicament for treating rheumatoid arthritis.
  2. 2. The use of claim 1, wherein the CK2 inhibitor is CX-4945, CX5011, BMS-595, BMS-211, POM, Tetrabromobenzotriazole (TBB), DMAT, TMCB, TTP 22, (E) -3- (2,3,4, 5-tetrabromophenyl) acrylic acid (TBCA) or ellagic acid.
  3. 3. The use of claim 1, wherein the therapeutic agent is an oral dosage form.
  4. 4. A therapeutic agent for rheumatoid arthritis, which comprises a CK2 inhibitor.
  5. 5. The medicament of claim 4, wherein the CK2 inhibitor is CX-4945, CX5011, BMS-595, BMS-211, POM, Tetrabromobenzotriazole (TBB), DMAT, TMCB, TTP 22, (E) -3- (2,3,4, 5-tetrabromophenyl) acrylic acid (TBCA), or ellagic acid.
  6. 6. The pharmaceutical of claim 5, wherein the CK2 inhibitor is CX-4945 in an oral dosage form.
CN202011103656.8A 2020-10-15 2020-10-15 Application of CK2 inhibitor in preparation of medicine for treating rheumatoid arthritis Pending CN112274642A (en)

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Cited By (1)

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CN116211860A (en) * 2023-05-10 2023-06-06 细胞生态海河实验室 Application of CK2 inhibitor CX4945 in preparation of medicines for preventing immune cell depletion in tumor treatment, inhibitor and combination

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116211860A (en) * 2023-05-10 2023-06-06 细胞生态海河实验室 Application of CK2 inhibitor CX4945 in preparation of medicines for preventing immune cell depletion in tumor treatment, inhibitor and combination
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