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ETS structural domain protein targeting inhibitor and application thereof

A domain protein and inhibitor technology, applied in the field of inhibitors targeting ETS domain proteins, can solve problems such as undiscovered

Active Publication Date: 2021-03-12
SHANTOU UNIV MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, currently, no clinically widely used inhibitors targeting proteins containing ETS domains have been found.

Method used

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  • ETS structural domain protein targeting inhibitor and application thereof
  • ETS structural domain protein targeting inhibitor and application thereof
  • ETS structural domain protein targeting inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Source of experimental materials:

[0034] Recombinant Human Transcriptional regulator ERG was purchased from CUSABIO; SeriesS Sensor Chip CM5 was purchased from Cytiva; Nifuratel, Nifuroxazide, Nifursol, Andrographolide, Olaparib and CCK8 were purchased from MCE; transcriptome sequencing was completed by Novogene.

[0035] Cell Proliferation Inhibition Experiment:

[0036] stay 75cm 2 When the growth confluence of the culture flask cells reached about 85%, the cells were digested, and 5000 VCap cells per well were inoculated on a 96-well plate, and the complete culture solution was 100 μl per well. After the cells adhered to the wall, different concentrations of Nifuratel, Nifuroxazide, Nifursol, and Andrographolide solutions prepared in complete medium were added, and the same amount of solvent DMSO was used as a control, and the incubator was incubated for 72 hours. The upper medium was removed, and 10 μl of CCK8 stock solution and 90 μl of the corresponding comple...

Embodiment 2

[0042] The sources of the experimental materials are the same as those in Example 1. Nifuroxazide is used as the representative of the acetylhydrazide derivatives and their analogues of the present invention, hereinafter referred to as NFZ, for experimental testing. Other acetylhydrazide derivatives and their analogues with similar structures have not been tested specifically, but those skilled in the art know that they can obtain similar experimental results.

[0043] 1. NFZ and ERG affinity determination

[0044] According to the provisions of USP40 IMMUNOLOGICAL TEST METHODS—SURFACE PLASMONRESONANCE (1105), ERG protein was immobilized on the CM5 chip, and NFZ was formulated into 100, 50, 25, 12.5, 6.25, 3.125, 1.5625 and 0 μM / L through the experimental channel in turn , using the same amount of solvent DMSO as a reference, and the detection is completed by Biacore8K. The result is as figure 1 shown.

[0045] according to figure 1 , the KD value of the affinity between N...

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Abstract

The invention relates to the field of targeted inhibitors, and discloses an ETS domain protein targeted inhibitor, which can be combined with a conservative domain ETS of ERG in a targeted manner andactivates parthanatos by blocking the combination of the ETS domain and PARP to influence the expression of parthanos to downstream genes; wherein most downstream genes are cytokines, and meanwhile, the up-regulation of DNA damage repair genes is caused. Therefore, the purpose of treating related diseases is achieved by blocking the combination of an ETS structural domain and other proteins.

Description

technical field [0001] The invention relates to the field of targeted inhibitors, in particular to an inhibitor targeting ETS domain protein and application thereof. Background technique [0002] In 2005, Tomlins et al. confirmed that in prostate cancer, TMPRSS2: ERG fusion is very common (about 50%). After fusion with the androgen-driven promoter of TMPRSS2 gene, the sustained high expression of ERG in prostate cancer will promote the development of prostate cancer. progress. Fusions increased in frequency from high-grade PIN (10–20%) to cancerous (30–80%), with 79% of fusion patients more likely to relapse. ERG and its family members (ETS1 / 2, ETV1, ETV6, FLI1, and ELK3, etc.) are also associated with other cancers, including Ewing's sarcoma and leukemia. For example, ERG-positive ALL was four times more likely to relapse than ERG-negative. Overexpression of ERG is one of the key factors in transforming locally invasive cancer into metastatic cancer. Members of this fam...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D307/33C07D307/75A61P31/14A61P31/18A61P35/00A61P35/02A61P31/20A61K31/422A61K31/341A61K31/704A61K31/136A61K31/513A61K38/14
CPCC07D413/12C07D307/33C07D307/75A61P31/14A61P31/18A61P35/00A61P35/02A61P31/20A61K31/422A61K31/341A61K31/704A61K31/136A61K31/513A61K38/14A61K2300/00
Inventor 大卫·凯尔文李成勋
Owner SHANTOU UNIV MEDICAL COLLEGE