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An inhibitor targeting ets domain protein and its application

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: 2022-07-08
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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  • An inhibitor targeting ets domain protein and its application
  • An inhibitor targeting ets domain protein and its application
  • An inhibitor targeting ets domain protein and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Source of experimental materials:

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

[0035] Cell proliferation inhibition assay:

[0036] Wait for 75cm 2 When the cell growth confluence in the culture flask reaches about 85%, the cells are digested, and 5000 VCap cells per well are seeded in a 96-well plate, and the complete culture medium is 100 μl per well. After the cells adhered, 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 incubated in an incubator for 72 hours. Remove the upper medium, add 10 μl of CCK8 stock solution and 90 μl of the corresponding complete med...

Embodiment 2

[0042] The source of the experimental material is the same as that of Example 1, and the following uses Nifuroxazide as the representative of the acetyl hydrazide derivative and its analogs of the present invention, hereinafter referred to as NFZ, to carry out the experimental test. Although no specific experiments have been carried out on other acetylhydrazide derivatives with similar structures and their analogs, those in the art know that familiar experimental results can be obtained.

[0043] 1. NFZ and ERG affinity determination

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

[0045] according to figure 1 , and the KD val...

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Abstract

The invention relates to the field of targeted inhibitors, and discloses an inhibitor targeting ETS domain proteins, which can target and bind to the conserved domain ETS of ERG, activate parthanatos by blocking the combination of the ETS domain and PARP, and affect its The expression of downstream genes, most of which are cytokines, also causes the up-regulation of DNA damage repair genes. By blocking the binding of the ETS domain to other proteins, the purpose of treating related diseases is achieved.

Description

technical field [0001] The present invention relates to the field of targeting inhibitors, in particular to an inhibitor targeting ETS domain proteins and applications thereof. Background technique [0002] In 2005, Tomlins et al. demonstrated that TMPRSS2:ERG fusions are very common (approximately 50%) in prostate cancer, and that after fusion with the androgen-driven promoter of the TMPRSS2 gene, persistent high expression of ERG in prostate cancer promotes prostate cancer progression. progress. The frequency of fusions increased from high-grade PIN (10–20%) to cancerous (30–80%), with 79% of fusion patients more likely to have a recurrence. 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 acute T-lymphoblastic leukemia was four times more likely to relapse than negative patients. Overexpression of ERG is one of the key factors in transforming lo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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