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Application of NIK protein kinase inhibitor in serving as medicine for treating liver diseases

A protein kinase inhibitor, drug technology, applied in the application field of NIK protein kinase inhibitor, acute liver injury, treatment of liver inflammation, liver fibrosis and liver cirrhosis

Inactive Publication Date: 2016-07-20
NORTHEAST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Whether these small molecule compounds can treat liver inflammation, liver injury, fibrosis and cirrhosis has not been reported

Method used

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  • Application of NIK protein kinase inhibitor in serving as medicine for treating liver diseases
  • Application of NIK protein kinase inhibitor in serving as medicine for treating liver diseases
  • Application of NIK protein kinase inhibitor in serving as medicine for treating liver diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Synthesis of NIK inhibitor B022.

[0026] Materials and Methods:

[0027] 2-Amino-5-chloropyrimidin-4-ol (2)

[0028] At room temperature, 2-aminopyrimidin-4-ol (1 g, 9.1 mmol), acetic acid (10 mL) and NCS (1.32 g, 10 mmol) were successively added into a round bottom flask, and reacted at 100oC for 1 h. The acetic acid was removed by rotary evaporation, and water (20 mL) was added. The precipitate was filtered off and dried under vacuum overnight. 720 mg of the target compound was obtained, and the yield was 54%. 1HNMR (DMSO-d6, 300MHz): 7.77(s, 1H), 6.83(s, 2H). ESI-MS theoretical calculation value C4H5ClN3O[M+H]+=146.01, experimental measurement: 145.75.

[0029] 4,5-dichloropyrimidin-2-amine (3)

[0030] 2-Amino-5-chloropyrimidin-4-ol (5.16g, 36.5mmol) and POCl3 (40mL, excess) were successively added to a round bottom flask, and reacted at 110oC for 3h. Add saturated NaHCO3 aqueous solution to adjust pH>8. The mixture was filtered and the filtrate w...

Embodiment 2

[0036] Example 2: The effect of B022 on the expression of NF-kB2 (p52) induced by NIK in Q293T cells was detected by luciferase reporter gene assay.

[0037] Materials and Methods:

[0038] Q293T cells

[0039] pShuttletrackNIK plasmid

[0040] pGL3NF-kB2 plasmid (with luciferase reporter gene)

[0041] βGal plasmid

[0042] A total of 6 experimental conditions were designed, namely:

[0043] (1) Double transfection of βGal plasmid and NF-kB2 plasmid, the concentration of B022 was 0 μM;

[0044] (2) Double transfection of βGal plasmid and NF-kB2 plasmid, the concentration of B022 was 0.5 μM;

[0045] (3) Double transfection of βGal plasmid and NF-kB2 plasmid, B022 concentration was 5 μM;

[0046] (4) Triple transfection with βGal plasmid, NIK plasmid and NF-kB2 plasmid, B022 concentration is 0 μM;

[0047] (5) Triple transfection with βGal plasmid, NIK plasmid and NF-kB2 plasmid, B022 concentration is 0.5 μM;

[0048] (6) Triple transfection with βGal plasmid, NIK plas...

Embodiment 3

[0052] Example 3: Western blot detection of the effect of B022 on the expression of NF-kB2 (p52) induced by NIK in Hep1 cells.

[0053] Hep1 cells were infected with βGal, NIK and p100 adenovirus single, double or triple, and the expression of NF-kB2 (p52) was detected by western blot.

[0054] Materials and Methods:

[0055] Hep1 cells

[0056] βGal, NIK and p100 adenoviruses

[0057] B022

[0058] A total of 5 experimental conditions were designed, namely:

[0059] (1) βGal single infection;

[0060] (2) p100 single infection;

[0061] (3) p100+NIK double infection, the content of NIK virus is 1 / 10 of p100, and the concentration of B022 is 0 μM;

[0062] (4) p100+NIK double infection, the content of NIK virus is 1 / 10 of p100, and the concentration of B022 is 0.5 μM;

[0063] (5) p100+NIK double infection, the content of NIK virus is 1 / 10 of p100, and the concentration of B022 is 5 μM;

[0064] Specific experimental steps:

[0065] (1) Preparation of Hep1 cells: spre...

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Abstract

The invention belongs to the technical field of chemical medicine and particularly relates to an NIK protein kinase inhibitor serving as medicine for treating liver inflammation, acute liver damage, liver fibrosis and liver cirrhosis.Experiment results show that the NIK inhibiter can inhibit activation of NIK-induced NF-kappaB2 in liver parenchyma cells, wherein the activation indicates that an inactive precursor p100 is converted into active p52.The activity of an NIK-induced NF-kappaB promoter can be inhibited.Expression of genes related to NIK-induced inflammation in liver parenchyma cells can be inhibited.CCL4-induced liver damage, inflammation and fibrosis can be inhibited.The medicine prepared from the NIK protein kinase inhibitor is achieved and has a remarkable effect on relieving and treating liver inflammation, damage, fibrosis and liver cirrhosis.

Description

technical field [0001] The invention relates to the technical field of chemical medicines, and specifically relates to the application of NIK protein kinase inhibitors as medicines for treating liver inflammation, acute liver injury, liver fibrosis and liver cirrhosis. Background technique [0002] NF-κB is an important transcription factor involved in life activities such as immune response, cell death and survival, and plays an important role in diseases such as cancer, inflammation, obesity, diabetes, liver injury and fibrosis1-6. [0003] The NF-κB family includes five members: p65(RelA), p50(NF-κB1), p52(NF-κB2), RelB and c-Rel, which form homologous or heterodimers in pairs2,3. At rest, NF-κB binds to its inhibitory protein IκB (including IκBα, IκBβ and IκBε), and does not exhibit transcriptional activity. There are two main pathways for the activation of NF-κB: canonical and noncanonical. Classical NF-κB activation is mainly triggered by pro-inflammatory cytokines...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61P1/16A61P29/00
CPCA61K31/506
Inventor 陈政赵玉军任骁萌李新志
Owner NORTHEAST NORMAL UNIVERSITY
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