Application of piperazine derivative as p53 molecule regulator

A technology of derivatives and protein regulators, applied in the field of piperazine derivatives as p53 molecular activity regulators, can solve the problems of strong inhibition or activation of p53 function, strong drug efficacy, etc., to maintain pluripotency, inhibit differentiation, The effect of broad application prospects

Active Publication Date: 2014-12-17
INST OF GENETICS & DEVELOPMENTAL BIOLOGY CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing p53 activity modulators are too potent, often leading to strong inhibition or activation of p53 function

Method used

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  • Application of piperazine derivative as p53 molecule regulator
  • Application of piperazine derivative as p53 molecule regulator
  • Application of piperazine derivative as p53 molecule regulator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Embodiment 1, the influence of G5 on the expression of p53 downstream gene MDM2 and p21

[0070] Mouse embryo fibroblast (MEF) was used to detect the effect of compound G5 on the mRNA expression level and protein expression level of p53 downstream genes MDM2 and p21, and the specific process was as follows.

[0071] After MEF cells were cultured for 24 hours with working solution containing G5 or DMSO, the mRNA and protein expression levels of p53 downstream genes MDM2 and p21 in MEF cells were detected by real-time PCR and Western Blot experiments.

[0072] (1) Detection of mRNA expression level by real-time PCR

[0073] a. Collect cells: Collect about 1x10 cells cultured in the working solution of the G5 drug group and the DMSO control group. 6 , washed once with ice PBS.

[0074] b. RNA extraction: Add 1ml TRIZOL reagent (Invitrogen) to different cells respectively, vibrate vigorously to mix, and let stand in ice for 15 minutes. Add 200 μl chloroform and shake vig...

Embodiment 2

[0095] Example 2, Regulation of G5 on p53 signaling network and pluripotency regulatory network

[0096] Mouse embryonic stem cells ESC2 were used to detect the effect of compound G5 on the p53 downstream gene signaling network and the mRNA expression levels of important pluripotency factors, and the specific process was as follows.

[0097] After culturing ESC2 cells for 24 hours with the working solution of G5 drug group and DMSO control group, the mRNA expression levels of p53 downstream signaling network and important pluripotency factors in ESC2 cells were detected by the analysis method of overall gene expression profile.

[0098] The overall gene expression profiling process is as follows:

[0099] Total RNA was extracted from mouse ESC2 cells cultured with the working solution of the G5 drug group and the DMSO control group using TRIzol reagent. 10 micrograms of biotin-labeled antisense RNA were hybridized with the mouse WG-62.0 expression chip, and the hybridization ...

Embodiment 3

[0106] Embodiment 3, the impact of G5 and Z7 on the efficiency of stem cell establishment

[0107] Induced mouse pluripotent stem cell iPS assay was used to evaluate the effects of compounds G5 and Z7 on the efficiency of stem cell establishment. The experimental procedure is described below.

[0108] (1) Separation of MEFs

[0109] 1. The 13.5-day-old pregnant mice were killed by neck breaking and disinfected with 75% alcohol;

[0110] 2. Quickly cut open the lower abdomen with dissecting scissors under sterile conditions, exposing the uterus arranged like a string of beads;

[0111] 3. Pull out all the uteri with curved forceps, cut off the attached tissues at both ends with dissecting scissors, and immerse all the strings of uteri in the pre-cooled PBS solution containing 2% P-S (double antibody);

[0112] 4. Rinse the clusters of uteri three times in pre-cooled PBS solution to remove blood cells and tissues attached to the surface of the uterus;

[0113] 5. Use ophthal...

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Abstract

The invention discloses an application of a piperazine derivative as a p53 molecule activity regulator. Mouse and human cell experimental results show that the piperazine derivative can regulate expression of p53 downstream genes, also can make growth and proliferation of normal cells maintained and make proliferation of cancer cells inhibited, and has wide application prospects in the field of cancer therapy. In addition, through regulation of p53 molecules, the piperazine derivative also can adjust a pluripotency signal network of stem cells, inhibit differentiation of the stem cells or maintain the pluripotency of the stem cells, thereby improving the line establishment efficiency of the pluripotent stem cells.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to the use of piperazine derivatives as regulators of p53 molecular activity. Background technique [0002] p53 protein is the most important anti-cancer gene in mammals, and it plays an important role in regulating cell cycle, controlling cell aging and apoptosis process and so on. As the most important tumor suppressor factor, the molecular functions of p53 include many key links such as inhibiting the accumulation of mutations, controlling the repair process of damaged DNA, and inducing the apoptosis process of severely damaged cells. It plays an important role in the maintenance of normal physiological functions of cells. The role is crucial (Vousden KH et al., Blinded by the Light: The Growing Complexity of p53. Cell 2009; 137: 413-431.). Recent studies have also shown that p53 plays an important role in the proliferation and differentiation of stem cells, regulating the pluripotenc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/495A61P35/00
Inventor 王秀杰周琪刘鑫张映佟曼郝捷王柳顾奇谢东芳白冬辉任少芳
Owner INST OF GENETICS & DEVELOPMENTAL BIOLOGY CHINESE ACAD OF SCI
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