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Application of bisindole maleimide derivatives in the preparation of drugs for the treatment of chronic myelogenous leukemia

A technology of bisindolemaleimide and methanesulfonic acid bisindolemaleimide is applied in the field of medicine and can solve the problems of insufficient curative effect, one-sided curative effect, drug resistance and the like

Active Publication Date: 2017-06-13
SHANGHAI JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the resistance, insufficient curative effect and one-sided curative effect of existing anticancer drugs, the development of new chemotherapeutic drugs is becoming a new research hotspot.

Method used

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  • Application of bisindole maleimide derivatives in the preparation of drugs for the treatment of chronic myelogenous leukemia
  • Application of bisindole maleimide derivatives in the preparation of drugs for the treatment of chronic myelogenous leukemia
  • Application of bisindole maleimide derivatives in the preparation of drugs for the treatment of chronic myelogenous leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Experiment of p53 activation by bisindolemaleimide IX

[0054] Main experimental materials:

[0055] MEF (primary cells) cell line, HCT116, Bisindolylmaleimide IX, DMEM medium and fetal bovine serum.

[0056] Material configuration:

[0057] 1. Dissolve Bisindolylmaleimide IX in PBS containing DMSO to make a stock solution with a concentration of 1mM.

[0058] 2. Cells of MEF (WT) and HCT116 were inoculated into a six-well plate, and 2 ml of DMEM medium containing 10% fetal bovine serum was added to each well.

[0059] 3. When the cells grow stably to about 70-80% of the area of ​​the culture dish, dosing treatment.

[0060] Dosing steps are as follows:

[0061] Add the Bisindolylmaleimide IX solution to 2ml of culture medium to make the final concentration 2.5μM. After culturing for 1, 2, 4 and 8 hours, aspirate the culture medium, wash the cells twice with pre-cooled PBS, and then lyse the cells with RIPA lysate Protein was extracted, and PBS cells adde...

Embodiment 2

[0062] Example 2 Experiment of DNA damage induced by Bisindolylmaleimide IX

[0063] Main experimental materials:

[0064] Cell lines MEF (WT), Bisindolymaleimide IX, and BaF3 (mouse pre-B lymphocyte) cell line transfected with bcr-abl gene were purchased from Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Concord Cell Bank). Bisindolylmaleimide IX was purchased from Cayman Corporation. Topoisomerase I Assay Kit TG 1015-1 was purchased from TopoGEN.

[0065] experimental method:

[0066] 1. Inoculate MEF (WT) cells into a twelve-well plate covered with sterile coverslips, and add 1 ml of DMEM medium containing 10% fetal bovine serum to each well. When the cells grew stably to about 70-80% of the area of ​​the culture dish, the cells were divided into two groups, one group was added with 5mM caffeine, and the other group was not treated. After 1 hour, 10 μl of 250 μM Bisindolylmaleimide IX was added to the two groups of media at a ratio of 1:100 t...

Embodiment 3

[0074] Example 3 Detection Experiment of Bisindolylmaleimide IX Blocking Cell Cycle and Inducing Cell Death

[0075] Main experimental materials:

[0076] MEF cells, human colon cancer cell lines HCT116(p53+ / +), HCT116(p53- / -). Propidium iodide was purchased from Suleibao Company. McCoy’s 5a cell culture medium (special for Saos-2 cell line) was purchased from Shanghai Sangon Biotechnology Co., Ltd., and DMEM and RPMI-1640 medium were purchased from Hyclone Company.

[0077] experimental method:

[0078] 1. Seed MEF (WT), HCT116 (p53+ / +), HCT116 (p53- / -) cells in 6-well culture dishes. Use 2ml of DMEM medium containing 10% fetal bovine serum to cultivate for 24 hours, when they reached 60%-70% of the total surface, the cells were treated with Bisindolylmaleimide IX of different concentrations (0 μM, 2 μM, 4 μM, 8 μM) for 24 hours Cells were harvested by trypsinization, resuspended in 200 μl of PBS, and after adding 1 ml of 100% ethanol, the cells were placed in a -20°C ref...

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Abstract

The invention relates to the field of medicines, in particular to application of a bisindolylmaleimide derivative in preparation of a medicament for treating chronic granulocytic leukemia. The invention discloses the application of the bisindolylmaleimide derivative in preparation of the medicament for treating the chronic granulocytic leukemia. Compared with the prior art, the application has the advantages that the bisindolylmaleimide derivative activates a cancer suppressor gene p53 by inducing DNA damage, so that the cell period is stopped at the stage G2 / M; the activity of topoisomerase is suppressed by suppressing an addictive dependent Raf-Erk passageway at the downstream of BCR-ABL, and the sensitivity of cells to the bisindolylmaleimide derivative is enhanced, so that the aim of treating BCR-ABL positive leukemia is fulfilled.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the application of bisindolymaleimide derivatives (Bisindolymaleimide) in the preparation of medicines for treating chronic myeloid leukemia. Background technique [0002] Tumor is a complex disease with multiple gene changes, multi-stage occurrence, and multi-factor participation. The World Health Organization (WHO) "Global Cancer Report 2014" stated that in 2012, there were 14 million new cancer cases worldwide, of which about 8.2 million died. About 50% of new cancer cases occurred in Asia, most of them in China. There were 3.07 million new cancer patients and 2.2 million deaths in China, accounting for 21.9% and 26.8% of the global total respectively. The report predicts that global cancer cases will show a rapid growth trend, from 14 million in 2012 to 19 million in 2025. Therefore, it is self-evident that the research and solution of tumor treatment problems is of great importanc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4045A61K31/404A61K31/454A61K31/496A61K31/437A61P35/02
CPCA61K31/404A61K31/4045A61K31/437A61K31/454A61K31/496
Inventor 李保界张辛刘慧娟贺林
Owner SHANGHAI JIAOTONG UNIV
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