Small-molecule compound for inhibiting liver fibrosis and application thereof

A small molecule compound and liver fibrosis technology, applied in the field of biomedicine, can solve the problem of lack of therapeutic drugs for liver fibrosis or liver cirrhosis

Active Publication Date: 2018-11-02
SHANGHAI ADVANCED RES INST CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although the PI3K / Akt signaling pathway has been studied in this field, there is still a lack of effective therapeutic drugs for liver fibrosis or cirrhosis

Method used

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  • Small-molecule compound for inhibiting liver fibrosis and application thereof
  • Small-molecule compound for inhibiting liver fibrosis and application thereof
  • Small-molecule compound for inhibiting liver fibrosis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1, the construction of liver fibrosis mouse

[0075] In order to verify the inhibitory effect of PI4KIIIα down-regulation on liver fibrosis, the inventors used CCl 4 A mouse model of liver fibrosis was constructed using the method. The model utilizes CCl 4 And the damage effect of ethanol on liver cells to force liver fibrosis in mice. During the continuous repair of liver damage, the degree of liver fibrosis will also continue to increase, resulting in excessive liver fibrosis and eventually developing into cirrhosis. In mice with liver fibrosis, liver cells were damaged and liver function impaired. The establishment of the mouse liver fibrosis model was judged by observing the damage of the liver after the tissue section of the liver.

[0076] After the modeling was completed, the livers of control group wild-type mice (CTRL) and hepatic fibrosis mice (Cirrhosis) were dissected and compared. It was found that the liver surface of CTRL mice was smooth an...

Embodiment 2

[0079] Example 2. The effect of down-regulating PI4KIIIα on liver fibrosis in mice

[0080] In order to find a biopharmaceutical suitable for inhibiting liver fibrosis, the inventors conducted extensive screening and found that down-regulating PI4KIIIα has an effect on mouse liver fibrosis.

[0081] As mentioned above, the inventors constructed Cirrhosis mice and Cirrhosis-PI4KA - / + , it was found that Cirrhosis-PI4KA - / +The liver fibrosis of mice was significantly alleviated compared with that of Cirrhosis mice.

[0082] From the perspective of the liver as a whole, Cirrhosis-PI4KA - / + Liver surface of mice compared to Cirrhosis mice

[0083] The surface of the liver is smoother, such as figure 2 .

[0084] From the pathological section, Cirrhosis-PI4KA - / + The arrangement of liver cells in mice is more regular and compact than that in Cirrhosis mice, such as image 3 .

[0085] Observe the inflammatory vesicles near the venous sinus, and find that the inflammatory v...

Embodiment 3

[0088] Embodiment 3, screening the compound that has inhibitory effect to primary HSC

[0089] According to the degree of down-regulation of α-SMA mRNA levels in the treatment group relative to the blank control group after treatment, the strength of the effect of some potential candidates on inhibiting HSC activation was determined.

[0090] Screening conditions: the down-regulation degree of PI4KA mRNA level is >70%, 30-70%, <30%,

[0091] The strengths of inhibiting HSC activation were +++, ++, +, respectively.

[0092] After screening a large number of candidate compounds, some compounds that inhibit the expression of PI4KA in primary HSCs are listed in Table 1. These compounds can significantly inhibit the mRNA level of PI4KA, thereby inhibiting liver fibrosis.

[0093] Table 1. Compounds and their inhibitory effects on primary HSCs

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PUM

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Abstract

The invention relates to a small-molecule compound for inhibiting liver fibrosis and an application thereof. A series of compounds that have inhibitory effects on the expression of PI4KA (encoded PI4KIIIalpha) or the enzyme activity of PI4KIIIalpha of primary HSC (hepatic stellate cells) are obtained by screening, and these compounds can significantly inhibit the mRNA level of PI4KA of HSC or theenzyme activity of PI4KIIIalpha to further reduce the mRNA level of alpha-SMA or type I collagen, thereby inhibiting liver fibrosis.

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically, the invention relates to a small molecular compound for inhibiting liver fibrosis and its application. Background technique [0002] Liver fibrosis is a reversible hepatic callus repair response that occurs when the liver is injured, mainly manifested as the accumulation of extracellular matrix (ECM). When liver injury continues to occur, the accumulation of ECM will lead to the replacement of liver parenchyma by callus, and eventually develop into cirrhosis. The accumulation of ECM is closely related to the activation of hepatic stellate cells (HSC), and HSC has always been the main target cell for the prevention and treatment of liver fibrosis. Studies have shown that the activation of HSCs is regulated by the PI3K / Akt pathway. PI3K is an intracellular phosphatidylinositol kinase that regulates cell growth, proliferation, and differentiation. Studies have shown that the PI3K...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P1/16
CPCA61K45/00
Inventor 黄福德蒋理想卢木鵬王文安焦常平
Owner SHANGHAI ADVANCED RES INST CHINESE ACADEMY OF SCI
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