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Anti-tumor pharmaceutical composition containing EZH2 inhibitor and polyunsaturated fatty acid inhibitor and application of anti-tumor pharmaceutical composition

A technology of unsaturated fatty acids and anti-tumor effect, applied in the field of medicine, can solve problems such as poor activity, improve theoretical significance and application value, and enhance the effect of anti-tumor effect

Active Publication Date: 2022-08-09
PEKING UNIV THIRD HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to solve the problem of poor activity of EZH2 inhibitors on solid tumors, and to provide a pharmaceutical composition comprising EZH2 inhibitors and polyunsaturated fatty acid inhibitors that can enhance the anti-tumor effect of EZH2 inhibitors. It provides a new way to safely and effectively use EZH2 inhibitors in the treatment of solid tumors (especially ovarian cancer)

Method used

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  • Anti-tumor pharmaceutical composition containing EZH2 inhibitor and polyunsaturated fatty acid inhibitor and application of anti-tumor pharmaceutical composition
  • Anti-tumor pharmaceutical composition containing EZH2 inhibitor and polyunsaturated fatty acid inhibitor and application of anti-tumor pharmaceutical composition
  • Anti-tumor pharmaceutical composition containing EZH2 inhibitor and polyunsaturated fatty acid inhibitor and application of anti-tumor pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Inhibition of histone methyltransferase activity of EZH2 can increase the expression of ELOVL2

[0062] The ChIP-seq and RNA-seq data from the previous study (PMID: 33163485) were analyzed to find lipid metabolism-related genes directly regulated by EZH2, such as ELOVL2 and FADS2.

[0063] RNA-seq data showed that the biosynthetic pathway of polyunsaturated fatty acids was significantly altered, the expression of genes such as ELOVL2 and FADS2 was increased in EZH2-KO SKOV3 cells, and the level of H3K27me3 in the regulatory region of the ELOVL2 promoter was decreased in EZH2-KO cells, The expression of ELOVL2 was up-regulated.

[0064] The specific experimental results are as figure 1 shown.

Embodiment 2

[0065] Example 2: GSK126 can affect polyunsaturated fatty acid metabolism in ovarian cancer cells

[0066] The metabolic profiles of SKOV3 cells treated with GSK126 or DMSO (Ctrl) were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS) system, and DHA and EPA were increased after GSK126 treatment. GSK126-treated ID8 cell tumor-bearing mice (for specific methods of tumor inoculation, see Section 3.4 of Example 3), blood triglyceride (TG) levels were also elevated (eg, figure 2 shown). These results suggest that GSK126 can affect polyunsaturated fatty acid metabolism in ovarian cancer cells.

[0067] The specific experimental method for metabolic profiling was as follows. After DMSO or GSK126 (15 μmol / L) treatment for 48 h, the cells were collected and mixed with 10 pre-cooled zirconia beads and 20 μL of deionized water in an Eppendorf Safelock microcentrifuge tube. The samples were homogenized for 3 min, and 150 μL of methanol cont...

Embodiment 3

[0068]Example 3: Combined with SC-26196 can enhance the inhibitory effect of GSK126 on SKOV3 cells

[0069] 3.1 Cell proliferation experiment

[0070] Cells were seeded in 96-well plates at approximately 5000 cells per well. After 24 hours treatment with GSK126 and / or SC-26196, the concentration and the number of repetitions are shown in the figure. Then on the IncuCyte S3 platform (Sartorius, Germany) using a phase contrast channel to image cells. Every 3 hours, four sets of phase contrast images were taken from different areas of each well using a 10X objective. Set the IncuCyte S3 image analysis software to detect cell edges and determine the percentage of cell confluence.

[0071] The cell viability was detected by the CCK-8 method. After culturing the cells in a 96-well plate for 48 hours, 10 μL of CCK-8 (Dojindo Laboratories, Rockville, MA, USA) was added to each well, and the absorbance was measured at 450 nm with a microplate reader after 1 hour.

[0072] 3.2...

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Abstract

The invention provides a pharmaceutical composition for enhancing the anti-tumor effect of an EZH2 inhibitor, the pharmaceutical composition comprises the EZH2 inhibitor and a polyunsaturated fatty acid inhibitor, and the polyunsaturated fatty acid inhibitor enhances the anti-lipid metabolism abnormal solid tumor effect of the EZH2 inhibitor. The invention also provides a related preparation of the pharmaceutical composition and application of the pharmaceutical composition in preparation of antitumor drugs. The invention provides a new thought for safely and effectively treating solid tumors, especially ovarian cancer, by using the EZH2 inhibitor clinically, and has a good clinical application prospect.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an anti-tumor drug composition comprising an EZH2 inhibitor and a polyunsaturated fatty acid inhibitor and its use in preparing an anti-tumor drug. Background technique [0002] Dysregulation of epigenetic regulation has long been recognized as a key factor affecting tumorigenesis and maintenance. Histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is the catalytic subunit of the epigenetic regulator Polycomb Repressive Complex 2 (PRC2), which can inhibit the growth of the epigenetic regulator through its histone methyltransferase activity. Lysine at position 27 of histone H3 undergoes trimethylation (H3K27me3) to inhibit target gene transcription, and is involved in the regulation of physiological or pathological processes such as cell cycle, cell senescence, cell differentiation, and cancer. The abnormal expression of EZH2 is closely related to the malignant progre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/496A61P35/00
CPCA61K45/06A61K31/496A61P35/00A61K2300/00Y02A50/30
Inventor 薛丽香霍霄郭正阳宋佳桂宋颖张腾瑞
Owner PEKING UNIV THIRD HOSPITAL
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