Use of astemizole, its salt or solvate in the preparation of medicines for preventing and/or treating malignant lymphoma

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

Inactive Publication Date: 2019-03-08
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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  • Use of astemizole, its salt or solvate in the preparation of medicines for preventing and/or treating malignant lymphoma
  • Use of astemizole, its salt or solvate in the preparation of medicines for preventing and/or treating malignant lymphoma
  • Use of astemizole, its salt or solvate in the preparation of medicines 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 the interaction of EZH2-EED

[0047] For fluorescence polarization experiments, EHZ2 polypeptide labeled with fluorescein isothiocyanate (FITC) was used as a tracer substrate. Add 20 μM EED protein, 5 μM tracer substrate and different concentrations of astemizole compounds in 100 μl buffer (25 mM BISTRIS, 500 mM NaCl, 1 mM DTT), and incubate at room temperature for 5 hours, then use a fully automatic multifunctional microplate reader (POLAR star Omega Microplate reader, 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 for 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...

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 the tracer substrate. In 100 μl buffer (25mM BISTRIS, 500mMNaCl, 1mM DTT), add 20μM EED protein and 5μM tracer substrate and different concentrations and different forms of astemizole salt or non-salt form compounds, respectively sulfate, hydrochloric acid For compounds in salt and non-salt forms, 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 sets of repetitions were set up for each group of experiments, and the experimental data were analyzed and drawn 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 a...

Embodiment 3

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

[0051]Protein thermal stability migration experiment, using RT-PCR instrument (7500Fast RT-PCR System (ABI)) to measure protein thermal stability, using Bis-ANS as fluorescent dye to monitor the change of fluorescence value of the system, excitation light and emission light wavelength respectively Set to 395nm and 492nm. Add 20 μM EED protein, 50XBis-ANS dye and astemizole compound in different concentrations into 20 μl buffer system (25 mM BISTRIS, 500 mM NaCl, 1 mM DTT). With 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 melting temperature (Tm) of EED protein at different compound concentrations was further calculated by Boltzmann fitting method. All experiments were set as three repeated gr...

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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 Patents(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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