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Small molecular compound for inhibiting PD-1/PD-L1 and application thereof

A PD-L1, PD-1 technology, applied in the field of medicine, can solve the problem of slow progress in the development of small molecule drugs

Active Publication Date: 2018-11-09
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the good development status of antibody drugs, the development of small molecule drugs is progressing slowly

Method used

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  • Small molecular compound for inhibiting PD-1/PD-L1 and application thereof
  • Small molecular compound for inhibiting PD-1/PD-L1 and application thereof
  • Small molecular compound for inhibiting PD-1/PD-L1 and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] The present invention uses a commercial PD-1 / PD-L1 inhibitor screening kit, which is a high-throughput kit developed based on Homogeneous Time-Resolved Fluorescence (HTRF). Mainly rely on the excited rare earth metal chelate to release energy and transfer to the luminescent group to generate detection signal. In the experiment, Tag1-PD-1 with tag 1 will bind to Tag2-PD-L1 with tag 2, and the chelated Eu 3+ After the Tag1 antibody and the Tag2 antibody with the luminescent group XL665, the antibodies will bind to their respective target proteins. In the absence of blocking agents, PD-1 and PD-L1 bind to each other, and the two fluorescent groups are close to each other. , fluorescence resonance energy transfer occurs, and a part of the energy will be transferred from the fluorescence donor Eu 3+ The group transfers to the fluorescent acceptor XL665 group, and generates fluorescence at 665nm, while the energy that has not been transferred will emit fluorescence at 620nm,...

Embodiment 2

[0040] Example 2 Inhibitory effect of compounds M355-0148, M355-0149, and M355-0152 on mouse melanoma in vivo

[0041] Ⅰ. Cell Culture

[0042] B16-F10 cells were cultured in 1640 complete medium (containing 10% FBS), and when the cells were in the logarithmic growth phase and the growth confluence reached 80%-90%, they were passaged by trypsinization.

[0043] Ⅱ. Tumor transplantation experiment of mouse melanoma B16-F10

[0044] (1) Grouping of mice

[0045]A total of 24 mice with basically the same growth status were taken and divided into 4 groups, including the control group, M355-0148, M355-0149, and M355-0152 groups; -0152 is a drug, and the dosage is 20mg / kg, administered by intragastric administration.

[0046] (2) Mice were inoculated with melanoma B16-F10 cells intradermally

[0047] ① Anesthetize the mouse: Invert the EP tube containing the melanoma B16-F10 cells for 6 times and draw up the cell culture medium to 0.4ml;

[0048] ② B16F10 cells were intradermal...

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Abstract

The invention discloses application of a compound or a pharmaceutically acceptable salt or ester or a solvate compound in the preparation of a PD-1 / PD-L1 small-molecule inhibitor medicament. Potentially active candidate molecules in the compound library are virtually screened out by computer simulation. By using the homogeneous time-resolved fluorescence technique, high-throughput screening of candidate molecule antagonistic PD-1 / PD-L1 binding is performed, and a compound with good activity is selected to perform mouse melanoma B16-F10 tumor-transplanting experiments. Then, it is confirmed that the compounds screened by the invention have the antitumor activity.

Description

technical field [0001] The invention relates to the use of a class of compounds or pharmaceutically acceptable salts, esters or solvates thereof in the preparation of PD-1 / PD-L1 inhibitor drugs, which belongs to the field of medicine. Background technique [0002] Programmed cell death protein 1 (programmed cell death protein 1, PD-1) is a type I transmembrane protein that is expressed in T cells and can down-regulate the function of the immune system. It consists of 288 amino acids, including the IgV region of the extracellular segment , the transmembrane segment and the intracellular portion. The intracellular portion of the protein has two key phosphorylation sites on the immunoreceptor tyrosine inhibitory motif and the immunoreceptor tyrosine conversion motif, which play a role in the inhibition of T cell signal transduction by PD-1. played an important role in the process. The natural binding ligands of PD-1 are programmed cell death ligand 1 (programmed death-ligand ...

Claims

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Application Information

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IPC IPC(8): C07D413/14A61P35/00A61K31/4245A61K31/4439
CPCA61P35/00C07D413/14
Inventor 柳军轩春晓谢小雪江经纬
Owner CHINA PHARM UNIV
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