Small-molecule inhibitor for degrading copper ion transport proteins Atox1 and CCS and application thereof

A small molecule inhibitor and transporter technology, which can be used in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc.

Inactive Publication Date: 2020-07-31
CHANGCHUN UNIV OF CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with ER-positive breast cancer and HER2-positive breast cancer, triple-negative breast cancer has the ch

Method used

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  • Small-molecule inhibitor for degrading copper ion transport proteins Atox1 and CCS and application thereof
  • Small-molecule inhibitor for degrading copper ion transport proteins Atox1 and CCS and application thereof
  • Small-molecule inhibitor for degrading copper ion transport proteins Atox1 and CCS and application thereof

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Experimental program
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preparation example Construction

[0044] A method for synthesizing a small-molecule inhibitor that specifically targets and degrades copper transporters Atox1 and CCS in triple-negative breast cancer cells according to the present invention, the steps are as follows:

[0045] Step 1: Synthesis of Intermediates

[0046] Add the degradation module in dichloromethane, add the linker, acid amine condensation reagent HATU and diisopropylethylamine at 0°C, and stir the reaction mixture at 20°C for 12 hours. After the reaction, use petroleum ether Purify the reaction mixture with ethyl acetate 1:3 mixed reagent to obtain the desired intermediate product;

[0047] Step 2: Synthesis of DA-PROTAC

[0048] The intermediate product was added in dichloromethane, and the targeting module, acid amine condensation reagent HATU and diisopropylethylamine were added at 0°C, and the reaction mixture was stirred at 20°C for 12 hours. Water 1:4 mixed reagents were used to purify the reaction mixture to obtain the final product DA...

experiment example 1

[0054] Experimental example 1, the application of DA-PROTAC in degrading Atox1 and CCS protein

[0055] will be 8×10 5 The MDA-MB-231 cells were inoculated in 6cm culture dishes and cultured with DMEM medium containing 10% FBS to obtain the MDA-MB-231 cell culture system. Add equal volumes of DMSO, DC_AC50 and different concentrations (100nM, 200nM, 500nM, 1000nM) of DA-PROTAC to the MDA-MB-231 cell culture system, and use western blotting to detect intracellular ATOX1 and CCS after 24 hours of treatment Level.

[0056] the result shows( figure 1 ): Under 200nM DA-PROTAC treatment, the protein levels of ATOX1 and CCS were significantly reduced. It shows that DA-PROTAC can degrade ATOX1 and CCS protein.

experiment example 2

[0057] Experimental Example 2. Application of DA-PROTAC in inhibiting the proliferation, migration and tumorigenesis of triple-negative breast cancer cells (MDA-MB-231).

[0058] 1. Application of DA-PROTAC in regulating tumor cell proliferation and migration

[0059] 1. The effect of DA-PROTAC on the proliferation ability of tumor cells

[0060] (1) MDA-MB-231 cells were inoculated into 6-well plates, 500 cells were inoculated in each well, and cultured in DMEM medium containing 10% (volume fraction) FBS to obtain the MDA-MB-231 cell culture system.

[0061] (2) Cells were treated according to the following treatment groups:

[0062] Treatment group 1 (DMSO): an equal volume of DMSO was added to the MDA-MB-231 cell culture system.

[0063] Treatment group 2 (DC_AC50): Add an equal volume of DC_AC50 (the solvent is DMSO) to the MDA-MB-231 cell culture system, so that the concentration of DC_AC50 in the cell culture system is 5 μM.

[0064] Treatment group 3 (DA-PROTAC): Add...

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Abstract

The invention relates to a small-molecule inhibitor for degrading copper ion transport proteins Atox1 and CCS and application thereof, and belongs to the field of molecular targeting drugs. The molecular formula of the small-molecule inhibitor is C46H50BrF2N7O8S2. The invention also relates to application of the small-molecule inhibitor in preparation of a medicine for inhibiting triple-negative breast cancer. Pharmacodynamic experiments prove that the tumor-forming ability of triple-negative breast cancer cells can be obviously inhibited in vivo by the inhibitor, thus providing a new thoughtfor clinically treating triple-negative breast cancer.

Description

technical field [0001] The present invention relates to the field of molecular targeted drugs, in particular to a small molecule inhibitor targeting at degrading copper ion transporter Atox1 and CCS and its application, in particular to a small molecule inhibitor targeting at degrading copper ion transporter Atox1 and CCS and its application in Application in inhibiting triple-negative breast cancer cell proliferation and tumorigenesis. Background technique [0002] Breast cancer is a common malignant tumor with high morbidity, high mortality and poor prognosis. Triple-negative breast cancer is the expression of estrogen receptor (enstrogen receptor, ER), progesterone receptor (progesterone receptor, PR) and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2, HER2). Cancer accounts for about 10-20% of all breast cancers. Compared with ER-positive breast cancer and HER2-positive breast cancer, triple-negative breast cancer has the characteris...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/4365A61P35/00
CPCC07D495/04A61P35/00
Inventor 赵翊丞宋光启马丹辉
Owner CHANGCHUN UNIV OF CHINESE MEDICINE
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