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The invention also discloses application of CDK7 targeting inhibitor in preparation of drugs for treating cytokine release syndrome

A technology of cytokines and inhibitors, applied in the field of preparation of drugs for the treatment of cytokine release syndrome, capable of solving problems such as different limitations or side effects

Active Publication Date: 2021-04-16
FUDAN UNIV SHANGHAI CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above clinical CRS treatment methods have different limitations or side effects

Method used

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  • The invention also discloses application of CDK7 targeting inhibitor in preparation of drugs for treating cytokine release syndrome
  • The invention also discloses application of CDK7 targeting inhibitor in preparation of drugs for treating cytokine release syndrome
  • The invention also discloses application of CDK7 targeting inhibitor in preparation of drugs for treating cytokine release syndrome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Comparative experiments on the inhibition of CDK-7-targeting small molecule drugs of THZ1, SY-1365, and BS-181 on related target molecules in an inflammation model

[0031] Monocytes (THP-1, human monocytic cell line) in the exponential growth phase were treated with 100ng / ml PMA for 24 hours to form macrophages (mTHP-1, human monocyte-induced macrophages), and then respectively Treat the 500ng / ml LPS-induced inflammation model with 30nM THZ1, 30nM SY-1365, 10μM BS-181, collect the cells, and perform western detection of related proteins. The results are as follows image 3 As shown, THZ1, SY-1365, and BS-181 all have the effect of inhibiting LPS-induced inflammation (see image 3 A), THZ1-CDK7, SY-1365-CDK7, and BS-181-CDK7 complexes all have a certain inhibitory effect on RNA Poly II2, 7 site serine phosphorylation (see image 3 B1); To sum up, THZ1 has the best anti-inflammatory effect.

Embodiment 2

[0032] Example 2: THZ1 targets CDK7-RNA Polymerase II complex to regulate gene transcription and western experiments

[0033] Monocytes in the exponential growth phase were treated with 100ng / ml PMA for 24 hours to form macrophages, then treated with different concentrations of THZ1 (0, 20, 40, 100, 200nM) for 30 minutes, and then collected at different time points (8, 24 hours), the cells were collected, and western detection of related proteins was carried out. Figure 4 Schematic diagram of THZ1 targeting CDK7-RNA Polymerase II complex to regulate gene transcription. Among them, A represents the schematic diagram of RNA Poly, the mRNA transcription complex that THZ1 targets and regulates CDK7; B represents the effect of THZ1-CDK7 complex on RNAPoly II2, 7-site serine phosphorylation in western experiments under different concentrations and different action times of THZ1. Inhibition of chemicalization: As time goes by, the inhibitory effect weakens; the inhibitory effect in...

Embodiment 3

[0034] Example 3: Bacterial infection model of THZ1 targeting CDK7-RNA Polymerase II complex

[0035] Figure 5 It is the qRT-PCR experiment result of the bacterial infection model in which THZ1 targets CDK7-RNA Polymerase II complex, among which, A shows that THZ1 can significantly inhibit interleukin IL1B, interleukin Expression of IL6, interleukin IL8, tumor necrosis factor TNFA and chemokine CXCL10 and other related inflammatory genes; B shows that THZ1 can significantly inhibit interleukin IL1B, interleukin Expression of IL6, interleukin IL8, tumor necrosis factor TNFA and chemokine CXCL10 and other related inflammatory genes; C shows that THZ1 can significantly inhibit interleukin IL1B in HFF-1 (skin fibroblasts) , interleukin IL6, interleukin IL8, tumor necrosis factor TNFA and chemokine CXCL10 and other related inflammatory gene expression; D shows that THZ1 can significantly inhibit leukocyte-mediated Expression of IL1B, interleukin IL6, interleukin IL8, tumor necro...

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Abstract

The invention discloses an application of a CDK7 targeting inhibitor in preparation of a medicine for treating cytokine release syndrome, which is verified by biochemical and animal model experiments as follows: (1) under proper concentration, the CDK7 targeting inhibitor inhibits the expression of super enhancers and transcription factors related to inflammatory factors such as stat1, IL-1 and IL-6, and thereby inflammatory signal pathways of immune cells such as macrophages, T cells and endothelial cells can be specifically regulated and controlled; (2) mouse death caused by acute inflammatory storm caused by bacterial or viral infection can be remarkably reduced, functional failure caused by inflammation of related organs is reduced, and obvious toxic and side effects are not found in the period. According to the results, the polypeptide has great significance in treatment of cytokine release syndrome caused by bacteria, viruses or immunotherapy.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the application of CDK7 targeting inhibitors in the preparation of drugs for treating cytokine release syndrome. Background technique [0002] Cytokine release syndrome (CRS), also known as "cytokine storm", refers to the rapid production of a large number of cytokines in the body after the immune system is strongly stimulated (such as viruses, bacteria, immune intervention and other factors). It is a severe inflammatory response syndrome. Infectious diseases such as novel coronavirus (COVID-19), SARS, influenza virus, bacteria and other infectious diseases, as well as immunotherapy such as CAR-T, will be accompanied by cytokine release syndrome in a certain proportion of patients, especially critically ill patients. When the above-mentioned pathogens initially attack the body, immune cells such as macrophages and neutrophils will release cytokines to recruit relative immune ce...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61P35/00A61P29/00A61P31/04A61P31/12
CPCY02A50/30
Inventor 苏锋涛陆雪官郭小毛魏也李冲卞慧芳
Owner FUDAN UNIV SHANGHAI CANCER CENT
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