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Medical use and medicinal composition of VSIG3 small-molecule inhibitors

A technology of composition and inhibitor, applied in the field of medicine

Active Publication Date: 2019-11-15
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] To date, there are no literature reports involving small molecule inhibitors of VSIG3

Method used

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  • Medical use and medicinal composition of VSIG3 small-molecule inhibitors
  • Medical use and medicinal composition of VSIG3 small-molecule inhibitors
  • Medical use and medicinal composition of VSIG3 small-molecule inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Expression and Preparation of Human VSIG3 Extracellular Protein

[0039] ExpiChO-STM Cells (Gibco, A29127), ExpiFecta mineTM ChO Transfection Kit (Gibco, A29129) were purchased from Thermofisher Scientific Company; human VSIG3-his plasmid was synthesized by Shanghai Jierui Biotechnology Co., Ltd.; sheep anti-VSIG3 antibody (AF4915) was purchased from American R&D Systems; sheep secondary antibody (CW0240S) was purchased from Kangwei Century Biotechnology Co., Ltd.; enhanced BCA protein concentration detection kit (P0009) was purchased from Beyond Biotechnology Co., Ltd.

[0040] 1. Recovery and culture of ExpiChO-STM cells

[0041] Take the frozen ExpiChO-STM cells out of liquid nitrogen, thaw them in a water bath at 38-39°C, and shake them constantly to make them melt quickly until only a small amount of ice cubes remain in the tube. Remove the cells from the water bath Take it out, spray it with 75% alcohol and open it in an ultra-clean bench, transfer the cell suspe...

Embodiment 2

[0076] Screening of Affinity Molecules of VSIG3 Protein by Competitive ELISA

[0077] Competitive ELISA method is used to screen the affinity molecules of VSIG3 protein, and the affinity of the screened object for VSIG3 protein can be characterized through simple co-incubation, washing and color development steps. Mainly rely on the reaction of horseradish peroxidase and TMB chromogenic solution to produce a color change for detection. During the experiment, the VSIG3 protein was coated on the microtiter plate by physical adsorption, and the non-specific binding sites that were not saturated by the protein at the bottom of the plate were removed after washing and blocking steps, and then the test object and VSIG3 specific antibody mixture were added. Finally, secondary antibody and TMB were added for color development, and the absorbance at 450 nm was detected. If the detection object does not bind to the VSIG3 protein, the detection antibody will completely react with VSIG3,...

Embodiment 3

[0108] Establishment of PBMC cell agonist model for identification of compound cell activity

[0109] CD3 antibody can bind to TCR on the surface of T cells to activate T cells, stimulate the proliferation of T cells and the secretion of interleukin 2. While the cells are activated, if there is an inhibitory signal produced by the VSIG3 protein in the system, the agonistic effect will be weakened. During the construction of the cell model, the agonist and VSIG3 protein were administered simultaneously, and the activation of T cells was judged by analyzing the secretion of cytokines in the cell supernatant.

[0110] 1. PBMC cell activation experiment

[0111] Day 1: Coating protein

[0112] The mixtures of CD-3 antibody and VSIG3 protein were respectively coated in 96-well plates. In the agonist group, CD-3 was diluted to 2.5 μg / mL with PBS, and in the inhibition group, the concentration of CD-3 antibody was kept constant, and different concentrations of VSIG3 protein were a...

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Abstract

The present invention discloses a medicinal use and a medicinal composition of VSIG3 small-molecule inhibitors, and concretely provides an application of compounds K284-3046 or E894-0141 or pharmaceutically acceptable salts or solvates thereof in the preparation of VSIG3 inhibitors. The structures of the compounds K284-3046 and E894-0141 are as shown in the description. The present invention provides the VSIG3 small-molecule inhibitors for the first time. Protein and cell level experiments are carried out to firstly find that the compounds K284-3046 and E894-0141 can significantly bind to a VSIG3 protein in order to promote the release of inflammatory factors such as IFN-gamma and IL-17A, so the compounds K284-3046 and E894-0141 can be used for tumor immunotherapy as the VSIG3 small-molecule inhibitors.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the medical application and pharmaceutical composition of a VSIG3 small molecule inhibitor. Background technique [0002] VISTA (V-domain Ig suppressor of T cell activation) is a new type of immune checkpoint molecule, a member of the immunoglobulin family, first reported by Li Wang's team in 2011. VISTA is mainly expressed in the spleen, bone marrow and other immune organs, which play an important role in autoimmune diseases. VISTA knockout mice were found to have immune cell infiltration in the lung, liver, and pancreas, and the accumulation of chemokines in the serum . In psoriasis model mice, VISTA regulates the progression of psoriasis by modulating the IL-23 / IL-17 inflammatory axis. At the same time, many studies have shown that VISTA is a key immune regulatory molecule in tumor immunity. Overexpression of VISTA in MCA105 tumor cells reduced tumor immune enhancement i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/056C07D239/95A61K31/517A61K31/436A61P35/00
CPCC07D491/056C07D239/95A61P35/00
Inventor 柳军孙宏斌李婷婷张陆勇江经纬
Owner CHINA PHARM UNIV
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