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Drug composition containing AKT inhibitor and IRE1 inhibitor and application of drug composition

A composition and inhibitor technology, applied in the field of medicine, to achieve the effects of inhibiting growth and cell clone formation, high safety, and low toxic and side effects

Active Publication Date: 2017-06-13
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no relevant research report on the combined use of AKT inhibitors and IRE1 inhibitors for anti-tumor

Method used

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  • Drug composition containing AKT inhibitor and IRE1 inhibitor and application of drug composition
  • Drug composition containing AKT inhibitor and IRE1 inhibitor and application of drug composition
  • Drug composition containing AKT inhibitor and IRE1 inhibitor and application of drug composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Effect of embodiment 1MK-2206 on the growth of esophageal cancer cells after being treated alone

[0033] First, detect the drug sensitivity of Kyse450, Kyse510, TE-1, Eca-109, EC9706 esophageal cancer cells to MK-2206 alone.

[0034]1. Experimental method

[0035] The tumor cells were inoculated into 96-well plates at the number of 4000-6000 cells per well. After the cells adhered to the wall (24 hours), the MK-2206 drug was diluted to a certain gradient concentration, and each concentration was set to 5 replicate wells, divided into experimental Group and zero group dosing. After 48 hours, use the MTT method to detect cell viability. Add 10 μl of MTT solution to each well and continue to incubate for 4 hours. Carefully suck out the liquid in the wells to avoid contact with crystals in the wells. Add 100 μl of DMSO to each well and shake on a constant speed shaker in the dark. . After the crystals are fully dissolved, read the OD value (wavelength 570nm, reference w...

Embodiment 2

[0038] Example 2 Effect of MK-2206 alone on mTOR / AKT pathway in esophageal cancer cells

[0039] Western blot method was used to detect the expression of mTOR / AKT pathway-related proteins in esophageal cancer cells Kyse450 and Kyse510 cells treated with MK-2206 alone or in combination. First, Kyse450 and Kyse510 cells were divided into 2 × 10 per well 5 cells at a density of 6 wells. After the cells adhered to the wall, the drug was administered according to Example 1. After 48 hours of treatment, the whole protein of cells in each group was collected respectively. After SDS electrophoresis, the protein was transferred to a PVDF membrane, blocked with 5% skimmed milk powder at room temperature for 1 hour, incubated with the primary antibody corresponding to the protein to be detected, and incubated overnight at 4°C. After 24 hours, the primary antibody was recovered, washed three times with TBST for 5 minutes each time, and then incubated with the secondary antibody for 1 h...

Embodiment 3

[0041] Example 3 Effect of MK-2206 combined with STF-083010 on the growth of esophageal cancer cells

[0042] Human esophageal cancer cells Kyse450 and Kyse510 cells were inoculated into 96-well plates at the number of 4000-6000 cells per well. After the cells adhered to the wall, 5 μM concentration of MK-2206 and 40 μM concentration of STF-083010 were added. After 48 hours of culture, each well was Add 10 μl of MTT solution with a concentration of 5 mg / ml, continue to incubate for 4 h, then discard the culture solution, add 100 μl of DMSO to each well, and shake on a constant speed shaker in the dark. After the crystals are fully dissolved, read the OD value (wavelength 570nm, reference wavelength 630nm) on a microplate reader, read the absorbance value of each well, and calculate the cell survival rate after the combination of the two drugs. Synergy comprehensive factor (Combination Index, CI) analysis was carried out with CompuSyn software, the results are shown in Figure...

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Abstract

The invention relates to a drug composition containing a AKT inhibitor and an IRE1 inhibitor and application of the drug composition in preparing drug for preventing and treating tumor. The AKT inhibitor is selected from MK-2206, Perifosine, Ipatasertib or AZD5363, and is MK-2206 preferably; the IRE1 inhibitor is selected from STF-083010, APY29 or 4u8C, and is STF-083010 preferably. The drug composition combines MK-2206 with STF-083010, a new treatment scheme is provided for tumor patients, growing of tumor cells and forming of cell cloning can be inhibited effectively, the drug composition has effect remarkably better than single use of MK-2306 or STF-083010, has additive or synergistic effect, has low toxic and side effect on normal cells, is high in safety and can be applied in the field of preparing anti-tumor drug.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a pharmaceutical composition containing an AKT inhibitor and an IRE1 inhibitor and application thereof. Background technique [0002] Cancer is a disease with a high mortality rate second only to cardiovascular diseases, and the number of cancer patients and deaths worldwide is increasing. Nearly half of the new cancer cases occurred in Asia, most of which were in China, which ranked first in the world in terms of new cancer cases. Especially in the four types of malignant tumors including liver cancer, esophageal cancer, gastric cancer and lung cancer, China ranks first in the number of new cases and deaths in the world. Although the treatment of these cancers is mainly based on surgery, since early patients generally have no obvious symptoms, many of the cancer patients diagnosed for the first time are already in the middle and advanced stages and have lost the ch...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/4375A61K31/381A61P35/00
Inventor 王绍祥王晓王一飞胡超智王绍其徐海朋
Owner JINAN UNIVERSITY
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