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Micromolecule STAT3 inhibitor WZ-2-033 and application thereof to preparation of medicines for treating breast cancer and stomach cancer

A technology of small molecules and inhibitors, applied in the field of medicine, can solve the problems of low oral bioavailability, low bioavailability, complex components, etc., and achieve good application prospects

Active Publication Date: 2020-09-15
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to factors such as poor in vivo stability, high toxicity, easy degradation, and low bioavailability of oligonucleotide and polypeptide inhibitors, their application is limited; natural compound inhibitors have complex components and multi-target effects. Whether to directly target STAT3 is still unclear, and the mechanism is unknown; small molecule compound inhibitors such as Stattic, Niclosamide, C188-9, BP-1-102 have insufficient specificity, low oral bioavailability, poor solubility, and unstable structure, etc. Optimize and improve druggability
Although STAT3 inhibitors have entered clinical trials (such as OPB-31121, OPB-51602, BBI-608, etc.), so far no STAT3 inhibitors have been approved for clinical treatment.

Method used

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  • Micromolecule STAT3 inhibitor WZ-2-033 and application thereof to preparation of medicines for treating breast cancer and stomach cancer
  • Micromolecule STAT3 inhibitor WZ-2-033 and application thereof to preparation of medicines for treating breast cancer and stomach cancer
  • Micromolecule STAT3 inhibitor WZ-2-033 and application thereof to preparation of medicines for treating breast cancer and stomach cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of WZ-2-033

[0045] 2-(2-(4-trifluoromethylphenyl)-7-methoxyimidazol[1,2-a]pyridin-3-yl)-N-(1,1-dioxybenzene[b] The structure of thiophen-6-yl)acetamide (I) is shown below

[0046]

[0047] The specific preparation process is

[0048] Step 1: Preparation of 2-(4-trifluoromethylphenyl)-7-methoxyimidazol[1,2-a]pyridine

[0049]

[0050] Add 600 mg (1 eq) of 2-amino-4'-methoxypyridine and 1 g (1 eq) of 2-bromo-4'-trifluoromethylacetophenone into a clean flask, followed by salt Sodium bicarbonate 660 mg (1.5 equivalents), dissolved in ethanol, stirred at 78°C, heated to reflux for 4 hours, detected by TLC, the reaction was complete, cooled to room temperature, spin-dried the solvent, extracted and separated with ethyl acetate and water, and combined the organic phases , dried over anhydrous sodium sulfate, spin-dried the solvent, and column chromatography (petroleum ether: ethyl acetate = 5:1, V / V) gave 0.9 g of a brownish-yellow solid, with a yield of...

Embodiment 2

[0065] Example 2: Compound WZ-2-033 small molecule compound inhibits the proliferation of breast cancer cells and gastric cancer cells

[0066] 1. Operation method

[0067] (1) Cell culture

[0068] Human embryonic kidney cells 293 (HEK-293T), breast cancer cells MDA-MB-231, MDA-MB231-4175 and HCC70 gastric cancer cells AGS and MGC-803 used in the present invention are all from the US ATCC cell bank.

[0069] Human embryonic kidney cell 293 (HEK-293T), breast cancer MDA-MB-231 and MDA-MB231-4175 cells were cultured in DMEM medium containing 10% fetal bovine serum and 1% double antibody, gastric cancer cells AGS, MGC- 803 and breast cancer cells HCC70 were cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% double antibody at 37°C, 5% CO 2 in a constant temperature incubator.

[0070] (2) Cell proliferation assay by CCK8 method

[0071] CCK8 reagent contains WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfobenzene)-2H-tetra azole monosodium...

Embodiment 3

[0074] Example 3: Compound WZ-2-033 Small Molecule Compound Inhibits Colony Formation of Breast Cancer and Gastric Cancer Cells

[0075] (1) Cell plate colony formation experiment

[0076] When a single cell proliferates for more than 6 generations in vitro, the cell population composed of its progeny becomes a colony or clone. Each clone contains more than 50 cells with a size between 0.3-1.0mm. The colony formation rate indicates the independent viability of the cells, so the effect of the compound on the viability of cancer cells can be determined by the cell plate colony formation assay.

[0077] Take breast cancer MDA-MB-231 and MDA-MB231-4175 cells in logarithmic growth phase, gastric cancer AGS and MGC-803 cells, digest and resuspend into a single cell suspension, count and inoculate at a density of about 500 cells / well in a six-well plate. After the cells adhered to the wall, set up the control group and the treatment group. The control group was added with the medi...

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PUM

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Abstract

The invention belongs to the technical field of medicine and pharmacy, and discloses an application of a micromolecule compound WZ-2-033 shown as below to medicines for treating breast cancer and stomach cancer. The compound can restrain proliferation, clone formation, migration and invasion of breast cancer cells and stomach cancer cells, and can induce apoptosis of the breast cancer cells and the stomach cancer cells. The compound exerts effects through influencing an STAT3 signal channel, can reduce the phosphorylation level (Y705) of the STAT3, can reduce STAT3 dimer formation, can reduceDNA combining capacity and transcriptional activity of the STAT3, and can further reduce the expression level of STAT3 target genes c-Myc, Bcl-xL and Mcl-1 so as to restrain activation of STAT3 signals and restrain the growth of the breast cancer cells and the stomach cancer cells. In an animal model, the compound can restrain the growth of stomach cancer cell transplanted tumors and has favorableapplication prospects.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to small molecule STAT3 inhibitor WZ-2-033 and its application in preparing and treating breast cancer and gastric cancer. [0002] technical background [0003] Breast cancer is the most common female malignant tumor. The incidence of breast cancer in the world has been on the rise since the late 1970s. One of eight women in the United States will suffer from breast cancer in their lifetime. Although the incidence of breast cancer in China is relatively low at present, since the 1990s, the incidence and mortality of breast cancer in my country have increased significantly, ranking among the top five in the world. In the treatment of breast cancer, surgery is still the main means of treatment of breast cancer, chemotherapy, radiotherapy and endocrine therapy as adjuvant therapy. With the in-depth research on breast cancer, the treatment methods have become more and more...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/437C07D471/04A61P35/00
CPCA61K31/437A61P35/00C07D471/04
Inventor 张小雷王元相刘培庆钟燕黄秋瑶
Owner SUN YAT SEN UNIV
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