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Small-molecule inhibitor AZIN32 and application of small-molecule inhibitor AZIN32 in pharmacy

A small molecule inhibitor, AZIN32 technology, applied in the field of biomedicine, can solve problems such as poor curative effect and patient side effects, and achieve the effects of reducing content, inhibiting growth, and interfering with cellular polyamine metabolism

Active Publication Date: 2019-06-28
QUANZHOU NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these inhibitors that directly target ODC are used as anti-tumor drugs in clinical practice, but the curative effect is not good. After the polyamine synthesis is inhibited, the polyamine in the extracellular environment can enter the cell through the polyamine transporter (polyamine transport) on the cell membrane to compensate for the decrease in the polyamine content in the cell caused by the inhibition of synthesis.

Method used

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  • Small-molecule inhibitor AZIN32 and application of small-molecule inhibitor AZIN32 in pharmacy
  • Small-molecule inhibitor AZIN32 and application of small-molecule inhibitor AZIN32 in pharmacy
  • Small-molecule inhibitor AZIN32 and application of small-molecule inhibitor AZIN32 in pharmacy

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Pharmacophore Screening Results

[0021] Taking the crystal structure of AZIN (3BTN.pdb) as the initial structure, the pocket detection module was used to find possible binding sites in the receptor, and a total of 5 possible binding sites were found. Combining the mutation data of the binding interface of AZ and AZIN, the pocket containing the most binding interface residues was selected for further screening of small molecule inhibitors. Based on the determined key amino acid residue characteristics of the active site, the pharmacophore model of the binding pocket was constructed using the pharmacophore method ( figure 1 ). The constructed pharmacophore model was used to search and screen the SPECS compound database, and the final screened compound was named the small molecule inhibitor AZIN32, which is available for purchase, and its specific structural formula is:

[0022]

Embodiment 2

[0024] Effects of Small Molecule Inhibitor AZIN32 on ODC, AZ, AZIN and Polyamine Contents in PC3 Cells

[0025] 1. Detection of ODC, AZ-1 and AZIN-1 protein content changes in PC3 cells by immunoblotting

[0026] The cells treated with the drug AZIN32 and the control group were collected and lysed with RIPA cell lysate for half an hour, then centrifuged at 12000rmp in a centrifuge to collect the protein, and then the protein was quantified by the BCA method. After electrophoresis separation, the same amount of protein in each group was electrophoretically transferred to PVDF membrane and blocked with 5% skimmed milk (20mmol / L Tris-HCl, 150mmol / L NaCl, 0.05% Tween-20, pH7.4) for one hour Afterwards, overnight incubation with anti-ODC, AZIN-1 and AZ-1 monoclonal antibodies, followed by incubation with polyclonal antibodies for one hour at room temperature. The protein expression was detected by ECL. The result is as figure 2 As shown, compared with the control cells, the ODC...

Embodiment 3

[0030] Antitumor Activity of Small Molecule Inhibitor AZIN32

[0031] AZIN32 effectively inhibits the growth and reproduction of human prostate cancer PC3 cells

[0032] Take PC3 cells in the logarithmic growth phase in 4×10 3 Inoculate a 96-well cell culture plate at a concentration of one per well, and after culturing for 24 hours, add 1640 medium containing the small molecule drug AZIN32 into the cell wells, so that the final concentrations of AZIN32 are 0 μM, 12.5 μM, 25 μM, 50 μM, 75 μM and 100μM (4 replicate wells for each group). At the same time, there were no drug control group and blank group. After continuing to culture for 24h, 48h and 72h respectively, remove the cell culture medium in the culture plate, add MTT reagent with a final concentration of 0.2g / L, incubate at 37°C for 4h, add DMSO 150μL, shake and mix well, and measure the absorbance at 570nm . Cell proliferation inhibition rate=(A control well-A experimental well) / A control well×100%.

[0033] MTT ...

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Abstract

The invention provides a small-molecule inhibitor AZIN32 of which structural formula is shown in the description. The small-molecule inhibitor AZIN32 can be applied to prepare a drug inhibiting antienzyme inhibiting factors. The AZIN32 can inhibit the proliferation of human prostate cancer PC3 cells, reduce the content of ODC protein and polyamine in the cells, change the growth cycle of the PC3 cells, and also induce the apoptosis of the PC3 cells.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a small molecule inhibitor AZIN32 and its application in pharmacy. Background technique [0002] Polyamines are basic regulators of cell growth and development, and precise regulation of polyamine metabolism is necessary for normal life activities. Studies have found that polyamine metabolic disorders are closely related to the occurrence and development of various diseases, including cancer, inflammation, atherosclerosis, stroke, renal failure and diabetes. The rapid division of cells is highly dependent on the polyamine content in the cells, so the total polyamine content in tumor cells is also significantly higher than that in normal cells. Studies have found that increasing the level of polyamines in cells can promote tumor growth, invasion and metastasis, while reducing polyamine levels can inhibit tumor cell proliferation, thus regulating polyamine metabolic pathways has become ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/25A61P35/00
Inventor 孙丽丹谢晓兰翁文婷吕凤娇
Owner QUANZHOU NORMAL UNIV
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