Use of CSF-1R kinase inhibitor

A technology of CSF-1R and uses, applied in the field of medicine, can solve the problems of reduced anti-tumor effect and the like

Active Publication Date: 2021-08-31
SHANGHAI RUNSHI MEDICAL TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Usually these adverse reactions are related to the dose, lowering the dose can reduce or alleviate the adverse reactions, but at the same time it often leads to a reduction in the anti-tumor effect

Method used

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  • Use of CSF-1R kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1: Effect of Compound I on CSF-1R Kinase Activity

[0078] 1. Test method Z'-LYTE TM Kinase Assay

[0079] Refer to Z′-LYTE TM Kinase Assay kit (PV3190, ThermoFisher) instructions for detection, the specific steps are as follows: Z'-LYTE TM Tyrosine 1Peptide Substrate, Phospho-peptide, 5X KinaseBuffer, ATP, Development Reagent B, Development Buffer, Stop Reagent, all reagents were equilibrated to room temperature and added sequentially. The effect of different concentrations of compounds on the activity of CSF-1R kinase (PR4598A, ThermoFisher) was detected. Multiple wells were taken for each concentration, and 4% DMSO was used as a co-solvent. After the reaction was completed, 5 μL of Development Reagent B diluted with Development Buffer (1:256) was added to all reaction wells, and after 1 hour of reaction at room temperature, 5 μl of Stop Reagent was added to all reaction wells to terminate the reaction, and the fluorescent signal was detected with Synerg...

Embodiment 2

[0094] Example 2: Effect of Compound I on CSF-1R-mediated Cell Proliferation and Survival of Primary Macrophages

[0095] 1. Test method

[0096] 1.1 Effect on the proliferation of CSF-1R highly activated mouse myeloid leukemia cell M-NFS-60

[0097] The CSF-1R highly activated mouse myeloid leukemia cell line M-NFS-60 cells in the logarithmic growth phase were inoculated into a 96-well culture plate at an appropriate density (the culture medium of the M-NFS-60 cells contained 62 ng / ml Human recombinant macrophage colony-stimulating factor (M-CSF)), 90 μL per well, cultured overnight, added different concentrations of compounds for 72 hours, and set solvent control group (negative control). After the compound has acted on the cells for 72 hours, add 10 μL of CCK-8 reagent to each well, place it in a 37°C incubator for 2-4 hours, and read it with a full-wavelength microplate microplate reader. The measured wavelength is 450nm.

[0098] 1.2 Effects on CSF-1-induced survival of...

Embodiment 3

[0110] Example 3: Compound I reverses the M2 polarization phenotype of macrophages

[0111] 1. Test method

[0112] BALB / c mice (female, 6 weeks old, healthy) were sacrificed, and their bone marrow cells were obtained from their femurs and tibias, treated with schistosomiasis and inoculated into 6-well culture plates at an appropriate density, 2 mL per well, 100 ng per well / mL CSF-1 factor was added to induce macrophages (Bone marrow-derived macrophages, BMDM). After 7 days of induction, the cell culture medium was replaced, and the CSF-1 factor at the same concentration as above was added, and at the same time, 10 ng / ml IL4 and 10 ng / ml IL13 were used to induce M2 polarization of macrophages. While inducing polarization, the appropriate concentration of compound and negative control wells were added, and after 48 hours, the cells were harvested for flow analysis.

[0113] Collect the cells in good condition, first wash them twice with PBS, after washing, resuspend each sam...

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Abstract

The application provides use of a CSF-1R kinase inhibitor, i.e., a compound with a general formula (A) or pharmaceutically acceptable salts thereof in preparation of drugs for treating CSF-1R kinase signal transduction channel related diseases or drugs for regulating immunity. Shown by in-vivo and in-vitro researches, the compound can be used for remarkably inhibiting the activity of a CSF-1R kinase; the compound can be used for remarkably inhibiting proliferation of a CSF-1/CSF-1R-driven mouse myeloid leukemia cell line, inhibiting survival of CSF-1-induced macrophages and reversing M2-leant polarization phenotypes of the macrophages, and the effect is superior to that of a drug Pexidartinib on the market; in a TAMs-enriched tumor model (MC38 model), the compound can be used for remarkably antagonizing a tumor immunity inhibiting microenvironment, and a remarkable antitumor drug effect is embodied; and the compound has an inhibiting action on tumors insensitive to immunity check point drugs, can be used for strengthening the treatment effect of the immunity check point drugs and has a very good clinical application prospect.

Description

[0001] This application claims the priority of the prior invention patent application submitted to the State Intellectual Property Office of China on February 28, 2020 with the application number 202010128115.4 and the title of the invention "A Use of a CSF-1R Kinase Inhibitor". This prior application is incorporated by reference in its entirety into this application. technical field [0002] The invention belongs to the field of medicine, and in particular relates to the application of a CSF-1R kinase inhibitor in the preparation of drugs for treating diseases related to CSF-1R kinase signal transduction pathway or improving tumor immunosuppression. Background technique [0003] As a functional whole, the indivisible tumor microenvironment plays an important role in tumor progression. Numerous stromal cells in the microenvironment, such as tumor-associated macrophages, dendritic cells (DC), regulatory T cells (Treg), fibroblasts, killer T cells, etc., promote tumor progress...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61P35/00A61P35/02A61P29/00A61P37/04
CPCA61K31/496A61P35/00A61P35/02A61P29/00A61P37/04C07D401/12A61K45/06C07K16/2818A61K39/3955A61K2300/00
Inventor 张翱耿美玉艾菁王彩霞彭霞张阳丁健
Owner SHANGHAI RUNSHI MEDICAL TECH CO LTD
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