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Application of Astemizole and salts or solvates thereof in preparing drug for preventing and/or treating malignant lymphoma

A technology for malignant lymphoma and astemizole, applied in the field of medicine, can solve the problems of poor tolerance of high-intensity chemotherapy drugs and an average survival rate of less than 50%, and achieve the effect of preventing and treating malignant lymphoma diseases

Inactive Publication Date: 2015-11-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the one hand, because the average age of onset of patients is over 50 years old, the tolerance to high-intensity chemotherapy drugs is poor, and the average 5-year survival rate is less than 50%.
Currently, there are no reports of inhibitors targeting the EZH2-EED protein-protein interaction

Method used

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  • Application of Astemizole and salts or solvates thereof in preparing drug for preventing and/or treating malignant lymphoma
  • Application of Astemizole and salts or solvates thereof in preparing drug for preventing and/or treating malignant lymphoma
  • Application of Astemizole and salts or solvates thereof in preparing drug for preventing and/or treating malignant lymphoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Fluorescence Polarization (FP) detection of the effect of astemizole on EZH2-EED interaction

[0047] For fluorescence polarization experiments, EHZ2 polypeptide labeled with fluorescein isothiocyanate (FITC) was used as a tracer substrate. Add 20 μM MEED protein, 5 μM tracer substrate and different concentrations of astemizole compound to 100 μl buffer (25mMBISTRIS, 500mMNaCl, 1mMDTT), incubate at room temperature for 5 hours, and use a fully automatic multifunctional microplate reader (POLARstar OmegaMicroplatereader, purchased from BMG .LABTECH) to detect the fluorescence polarization value. The excitation and emission wavelengths used were 480 nm and 520 nm, respectively. Three groups of repeated experiments were set up in each group, and the experimental data were analyzed and drawn using GraphPad Prism 5.0 software. The experimental results are as follows figure 1 shown. This result indicates that astemizole can compete with EZH2 polypeptide for bind...

Embodiment 2

[0048] Embodiment 2: Fluorescence polarization method (FP) detects the influence of astemizole salt on EZH2-EED interaction

[0049] FITC-labeled EHZ2 polypeptide was used as tracer substrate. In 100μl buffer (25mMBISTRIS, 500mMNaCl, 1mMDTT), add 20μM EED protein and 5μM tracer substrate and different concentrations and different forms of astemizole salt or non-salt form compounds, namely sulfate, hydrochloride and For compounds in non-salt form, after incubation at room temperature for 5 hours, the fluorescence polarization value was detected with a fully automatic multi-functional microplate reader. The excitation and emission wavelengths used were 480 nm and 520 nm, respectively. Three groups of repetitions were set up for each group of experiments, and the experimental data were analyzed and graphed using GraphPad Prism 5.0 software. The experimental results are as follows figure 2 shown. The results indicated that the salt form of astemizole could also compete with EZ...

Embodiment 3

[0050] Example 3: Using the protein thermal stability shift method (ThermalShift) to detect the effect of astemizole on the thermal stability of EED protein.

[0051] Protein thermal stability migration experiment, using RT-PCR instrument (7500FastRT-PCRSystem (ABI)) to measure protein thermal stability, using Bis-ANS as a fluorescent dye to monitor the change of the fluorescence value of the system, and setting the excitation light and emission wavelength respectively for 395nm and 492nm. Add 20 μM EED protein, 50XBis-ANS dye and astemizole compound in different concentrations in 20 μl buffer system (25mMBISTRIS, 500mMNaCl, 1mMDTT). At a heating rate of 1%, the temperature of the system was gradually raised from 25°C to 95°C, and the change of fluorescence intensity was recorded at the same time, and the dissolution temperature (Tm) of EED protein at different compound concentrations was calculated by Boltzmann fitting method. All experiments are all set as three repetition ...

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Abstract

The invention relates to applications of astemizole shown in formula (I) pharmaceutically acceptable salts or solvates thereof in preparing drugs for preventing and / or treating malignant lymphoma, an application of astemizole and pharmaceutically acceptable salts or solvates thereof as an inhibitor of polycomb repressive complex 2 (PRC2), and an application astemizole and pharmaceutically acceptable salts or solvates thereof as an inhibitor for EZH2-EED interaction. Malignant lymphoma is a disease related to B-cell lymphoma of the germinal center, and comprises hodgkin lymphoma and non-hodgkin lymphoma. In addition, astemizole, and the pharmaceutically acceptable salt or solvate thereof can be put in combination use with the EZH2 inhibitor. The formula (I) is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to the use of an astemizole compound (Astemizole) represented by formula (I) and its pharmaceutical composition in the preparation of drugs for the prevention and / or treatment of malignant lymphoma, and as a polycomb inhibitor Use of inhibitors of complex 2. Background technique [0002] Astemizole is a second-generation histamine H1 receptor antagonist, which has the characteristics of fast absorption, strong antagonism of histamine receptors, and long duration. Astemizole is one of the trade names of the drug. It was first put into clinical use in the UK in 1983. The indications for its early listing include allergic rhinitis, allergic conjunctivitis, chronic urticaria and other allergic diseases. Allergy medication. However, due to its cardiotoxicity, astemizole has been withdrawn from the market in many countries. In recent years, it has been found that astemizole can inhibit the growth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/454A61P35/00
Inventor 罗成孔祥谦陈丽敏蒋翔锐杜道海卢俊彦刘静秋朱孔凯李连春丁宏陈凯先沈敬山蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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