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Application of c-Abl inhibitor in preparation of medicine for preventing and/or treating amyotrophic lateral sclerosis

A lateral sclerosis, c-abl technology, applied in the direction of drug combination, pharmaceutical formula, organic active ingredients, etc., can solve the effect of amyotrophic lateral sclerosis, the effect is not satisfactory, and the amyotrophic lateral sclerosis cannot be completely cured. Accordion sclerosis and other problems, to achieve the treatment or improvement of significant, significant effect

Active Publication Date: 2022-07-08
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The inventors have found that at least the following problems exist in the prior art: the only currently approved drugs for the treatment of ALS are riluzole and edaravone. However, the target of riluzole is Glutamate and edaravone are used to treat free radicals in the brain. The prevention and treatment of these two drugs are not very effective in the prevention and treatment of amyotrophic lateral sclerosis, and they cannot be completely cured to achieve amyotrophic lateral sclerosis. disease

Method used

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  • Application of c-Abl inhibitor in preparation of medicine for preventing and/or treating amyotrophic lateral sclerosis
  • Application of c-Abl inhibitor in preparation of medicine for preventing and/or treating amyotrophic lateral sclerosis
  • Application of c-Abl inhibitor in preparation of medicine for preventing and/or treating amyotrophic lateral sclerosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1. Experiment on degradation of TDP-43 and its related protein aggregates by SC75741

[0106] SH-SY5Y cells in 2*10 5 cells / mL, seeded in 6-well plates at a density of 2 mL per well. After 24 hours, GFP, GT43WT (TDP-43), GT35 (TDP-35), GT25 (TDP-25), GT43 A315T (TDP-43A315T) plasmids were transfected. After 24 hours, cells were treated with SC75741 for 24 hours at a final concentration of 5 μM. Samples were collected with 200 μL of 2XSDS loading buffer. Heating at 100°C for 10 minutes. Immunohybridization: Load 10 μL of each sample, electrophoresis at 100V for 2h; transfer to membrane at 300mA for 1h. 5% skim milk was blocked at room temperature for 1 h, and the antibodies (GFP antibody were purchased from Hangzhou Huaan Biotechnology Co., Ltd., #EM1607-31; Tubulin antibody was purchased from Hangzhou Huaan Biotechnology Co., Ltd., #M1305-2) at a certain dilution ratio (Tubulin antibody was 1:5000, the rest are 1:1000), incubate overnight at 4 degrees, and ...

Embodiment 2

[0112] Example 2. SC75741 degrades amyotrophic lateral sclerosis-related protein aggregate SOD1

[0113] SH-SY5Y cells were seeded in 6-well plates at a density of 2*105 cells / mL, with 2 mL per well. After 24 hours, GFP, GFP-SOD1 G93A (SOD1 G93A mutation produces aggregates) plasmid was transfected. After 24 hours, cells were treated with SC75741 for 24 hours at a final concentration of 5 μM. Samples were collected with 200 μL of 2XSDS loading buffer. Heating at 100°C for 10 minutes. Immunohybridization: Load 10 μL of each sample, electrophoresis at 100V for 2h; transfer to membrane at 300mA for 1h. 5% skim milk was blocked at room temperature for 1 hour, incubated at a certain dilution ratio (1:5000 for Tubulin antibody, and 1:1000 for the rest) overnight at 4 degrees, washed with PBST (phosphate buffered saline + 0.1% Tween20) 3 times for 10 minutes each time . Secondary antibodies (Goat anti-Mouse IgG (H+L) secondary antibodies were purchased from Thermo Fisher Scienti...

Embodiment 4

[0118] Example 4. SC75741 target NF-κB is not involved in SC75741-induced degradation of TDP-43 and its related protein aggregates

[0119] H4GT25 cells (a cell line constructed in this experiment that express TDP-25 induced by doxycycline (Dox) in H4 cells) were seeded in 6-well plates at a density of 2*105 cells / mL, with 2 mL per well. Add 1 μg / μL Dox for 24 h. Add SC75741 (5μM), NF-κB inhibitor: CAPE (10μM), JSH-23 (10μM) for 24 hours. Samples were collected with 200 μL of 2XSDS loading buffer. Heating at 100°C for 10 minutes. Immunohybridization: Load 10 μL of each sample, electrophoresis at 100V for 2h; transfer to membrane at 300mA for 1h. 5% skim milk was blocked at room temperature for 1 h, antibodies (GFP antibody were purchased from Hangzhou Huaan Biotechnology Co., Ltd., #EM1607-31; phospho-c-Abl (Tyr245) was purchased from Cell Signaling #2861; Tubulin antibody was purchased from Hangzhou Huaan Biotechnology Co., Ltd., #M1305-2) at a certain dilution ratio (1:...

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Abstract

The invention discloses an application of a c-Abl inhibitor in preparation of a medicine for preventing and / or treating amyotrophic lateral sclerosis. In the application, the invention provides an application of c-Abl protein as a target in screening of drugs for preventing and / or treating amyotrophic lateral sclerosis, an application of SC75741 in preparation of drugs for preventing and / or treating amyotrophic lateral sclerosis, and the like. The c-Abl inhibitor provided by the invention can induce degradation of proteins expressed by amyotrophic lateral sclerosis related pathogenic genes and mutants of the proteins; according to the application, a nervous system model proves that the SC75741 has a remarkable treatment or improvement effect on amyotrophic lateral sclerosis.

Description

technical field [0001] The embodiments of the present invention relate to the field of chemical medicines, in particular to the application of c-Abl inhibitors in the preparation of medicines for preventing and / or treating amyotrophic lateral sclerosis. Background technique [0002] Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with progressive muscle denervation, weakness, atrophy, spasticity, paralysis and eventual death. About 90% of amyotrophic lateral sclerosis cases are sporadic (sALS) and only 10% are familial amyotrophic lateral sclerosis (fALS). [0003] The inventors found that there are at least the following problems in the prior art: the only drugs that have been approved and marketed for the treatment of amyotrophic lateral sclerosis are riluzole and edaravone, however, the targets targeted by riluzole For glutamate and edaravone to achieve treatment by scavenging free radicals in the brain, the prevention and treatment of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/519A61P21/00A61P25/28
CPCA61K45/00A61K31/519A61P21/00A61P25/28
Inventor 夏宏光周东恒岑旭峰吴荣海
Owner ZHEJIANG UNIV
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