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Target anti-cancer medicine based on STAT3 (Signal Transducers and Activators of Transcription type 3) protein target spot

A drug and cancer technology, applied in the field of signal transduction system inhibitor compounds, can solve the problems of no improvement in the biological activity of compounds, difficulty in modifying natural compounds, and easy drug resistance

Inactive Publication Date: 2017-05-17
HENAN RADIOMEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other STAT3 inhibitors reported in international related research include: STAT 21 (the biological activity of the second-generation optimized compound is not improved), STATTIC (there is no structural model of compound-protein interaction, and there is no way to start the structure optimization) and the Chinese University of Hong Kong. Cucurbitacin I that inhibits nasopharyngeal carcinoma (natural compound modification is difficult)
In short, the targets of targeted anticancer drugs currently used in clinical treatment tend to be upstream of the cell signal transduction pathway, which is likely to cause drug resistance, and the drug under development based on the STAT3 target can effectively overcome this weakness

Method used

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  • Target anti-cancer medicine based on STAT3 (Signal Transducers and Activators of Transcription type 3) protein target spot
  • Target anti-cancer medicine based on STAT3 (Signal Transducers and Activators of Transcription type 3) protein target spot
  • Target anti-cancer medicine based on STAT3 (Signal Transducers and Activators of Transcription type 3) protein target spot

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1: Molecular docking (docking) experiment

[0022] METHODS: In order to provide a set of reasonable computer-predicted selective target-attack chemical probes for Stat3, we used the phosphorylated tyrosine (pY-705) binding region of the SH2 region of Stat3 as the docking site, It mainly includes phosphorylated tyrosine interaction site R609 and hydrophobic interaction site W623. The structural coordinates of Stat3 SH2 were obtained from the protein structure database (PDB data bank, ID: 1BG1). The selected chemical compound library is LIFE CHEMICALS. Molecular docking method: All computer coordination simulation (docking) experiments were completed on the Schrodinger-Maestro operating platform, and the computer coordination simulation (docking) tool used was Glide. First, take Stat3 SH2 out of the PDB data bank and download it to the Schrodinger operating platform - Maestro. After dehydration, add hydrogen atoms and charges to the amino acids of Stat3 SH2 ...

Embodiment 2

[0023] Example 2: BIAcore experiment

[0024] Method: The experiment of the interaction between the selected compound and Stat3 molecules (BIAcore) is at 25°C, the phosphorylated polypeptide is immobilized on the BIAcore 3000 biochip (biosensor) attached to streptavidin, and the flow buffer used is 20mM at pH8 Concentration of Tris buffer contains 2mM concentration of mercaptoethanol and 5% DMSO aqueous solution, and its flow rate is 10uL / min. Before the test, Stat3 protein at a concentration of 500nM was mixed with the selected compound to a predetermined concentration of 0.1, 0.5, 1, 5, 10, 50, 100, 500uM. After each test, the biosensor was rinsed with 10 uL of 100 mM glycine at pH 1.5 for the next test. Stat3 protein at 500 nM without drug mixture was tested once from start to finish to ensure that the entire test system was always functioning normally (6). Experimental (BIAcore) result analysis: The characteristic curve of the BIAcore signal of different concentrations o...

Embodiment 3

[0025] Example 3: Western blot

[0026] Method: Experimental method of Western blot: Human hepatocellular carcinoma cells (HepG2) were cultured in a six-well plate under standard conditions. Cells were treated with compounds at different concentrations - 0.5, 1, 5, 10 (uM) and incubated for 1 hour. Cells were treated with IL-6 at a concentration of 30 ng / ml and incubated for half an hour to stimulate Stat3 phosphorylation. After the cells are harvested, proteins are isolated using high-salt buffer. The separated protein was mixed with SDS and heated at 100°C for 5 minutes. Perform electrophoresis on SDS-PAGE polyacrylamide gel to distinguish and fix proteins of different masses, then transfer the protein to PVDF membrane and cover the PVDF membrane with BSA. Molecular weight markers were embedded in SDS-PAGE gels and transferred to PVDF membranes. Use anti-phospho-pY705-Stat3 primary antibody and anti-total Stat3 primary antibody to detect phosphorylated pY705-Stat3 and to...

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Abstract

The invention relates to a target anti-cancer medicine based on an STAT3 (Signal Transducers and Activators of Transcription type 3) protein target spot. Cell lines of a plurality of types of breast cancers have an abnormal regulation and control mechanism of an intracellular STAT3 signal conduction system. The invention provides one type of compound, which is an effective regulator of STAT3 signal conduction, and can be applied to preparation of medicines for treating breast cancer.

Description

technical field [0001] The invention relates to the application of a signal transduction system inhibitor compound in the preparation of medicines for treating cancer. Background technique [0002] Cancer has become one of the factors affecting the health of Chinese nationals and causing significant economic losses. The traditional methods of cancer treatment - surgery, radiotherapy, chemotherapy and biological therapy have certain limitations in controlling the condition of tumor patients. In 2001, the advent of Gleevec, the first-generation targeted drug, brought new opportunities and hopes to the clinical treatment of cancer patients, and has the advantages of significant clinical efficacy and less toxic side effects. The only targeted drug independently developed in China for the treatment of nasopharyngeal carcinoma-Icotinib targets the epidermal growth factor receptor (EGFR), which is similar to the target of gefitinib for the treatment of non-small cell lung cancer ...

Claims

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Application Information

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IPC IPC(8): A61K31/4196A61P35/00
Inventor 徐学军谢盼盼卞龙骧
Owner HENAN RADIOMEDICAL SCI & TECH CO LTD
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