EGFR and CDK4/6 small molecule targeted drug composition and application thereof

A technology of small molecules and compositions, which is applied in the field of preparation of drugs that inhibit the growth of colorectal cancer cells, and can solve the problems of unrecognizable and combined effects of macromolecular monoclonal antibody drugs, uncontrolled proliferation of cells, hyperactivity of cell cycle, etc. , achieve the effect of improving drug sensitivity, inhibiting cell proliferation, and broad application prospects

Inactive Publication Date: 2021-01-05
NANJING MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the structure of EGFR mutation changes, and macromolecular monoclonal antibody drugs cannot combine with its recognition to exert curative effect. Therefore, it is more suitable to use EGFR small molecule inhibitors for the treatment of this part of patients.
Recent studies have reported that in colorectal cancer, the amplification of the Rb signaling pathway and the increased release of the transcription factor E2F lead to the hyperactivity of the cell cycle and the uncontrolled proliferation of cells

Method used

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  • EGFR and CDK4/6 small molecule targeted drug composition and application thereof
  • EGFR and CDK4/6 small molecule targeted drug composition and application thereof
  • EGFR and CDK4/6 small molecule targeted drug composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Alamar blue was used to detect the proliferation of Palbociclib single drug in colorectal cancer cell lines, and the IC50 value was calculated. The specific implementation plan is as follows:

[0039] 1. The day before, HT29, HCT116, DLD1, HCT15, and LOVO were planted in 96-well plates at 1000 cells per well, and 3 replicate wells were plated for each concentration of each cell, and a control group was set.

[0040] 2. Prepare Palbociclib single-drug concentrations of 1nM, 10 nM, 100 nM, 300 nM, 500 nM, 1μM, 2μM, 4μM, 8μM, 10μM.

[0041] 3. After the cells adhere to the wall in step 1, the old medium is discarded, and then 100 μL of the mixture of complete medium and 10 μL of Lamar Blue is added to each well. After incubation in a cell culture incubator with 5% carbon dioxide at 37°C for 4 hours, use a chemiluminescence instrument to Under the conditions of excitation light wavelength 534nm and emission light wavelength 584nm, the absorbance was detected and the data of...

Embodiment 2

[0051] Western blot was used to detect the changes in the signaling pathways of HT29, DLD1, and HCT15 colorectal cancer cell lines under different concentrations of Palbociclib monotherapy. The specific implementation plan is as follows:

[0052] 1. Press the HT29, DLD1, HCT15 cell lines one day in advance by 6ⅹ10 5 / Dish spread in 6cm dishes, 6 dishes for each kind of cells.

[0053] 2. Prepare single drug Palbociclib with concentrations of 10nM, 50nM, 100nM, 500nM, 1 μM.

[0054] 3. Add 5mL of the drug in step 2 to each plate 24 hours after the cells are plated, and add DMSO with a concentration of 2‰ to the control group for 24 hours.

[0055] 4. After 24 hours of drug treatment, wash the cells twice with PBS, drain, add 200 μL of cell lysate to each dish, collect the lysed cells into a 1.5mL EP tube with a scraper, and then lyse at 4°C for half an hour, 13000rpm Centrifuge for 15 min to take the supernatant and store at -80°C.

[0056] 5. Measure the protein content of ...

Embodiment 3

[0060] Alamar blue was used to detect the cell proliferation of Erlotinib and Palbociclib under single-drug and two-drug combination, and the CI value was calculated. The specific implementation plan is as follows:

[0061] 1. The day before, HT29, HCT116 and LOVO cells were planted in a 96-well plate according to 1000 cells per well, and 3 replicate wells were plated for each concentration of each cell, and a control group was set.

[0062] 2. Prepare single drug Palbociclib 50nM, 100nM, 250nM, 500nM, 1μM and 2μM; single drug Erlotinib 500nM, 1μM, 2.5μM, 5μM, 10μM and 20μM; and any combination concentration of all concentrations of the two drugs.

[0063] 3. After the cells adhere to the wall in step 1, the old medium is discarded, and then 100 μL of the mixture of complete medium and 10 μL of Lamar Blue is added to each well. After incubation in a cell culture incubator with 5% carbon dioxide at 37°C for 4 hours, use a chemiluminescence instrument to Under the conditions of ...

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Abstract

The invention relates to an EGFR and CDK4 / 6 small-molecule targeted drug composition and application thereof. The EGFR and CDK4 / 6 small-molecule targeted drug composition is composed of two targeted drugs of an EGFR small-molecule inhibitor and a CDK4 / 6 small-molecule inhibitor, wherein the EGFR small-molecule inhibitor is Erlotinib, and the CDK4 / 6 small molecule inhibitor is Palbociclib. According to the EGFR and CDK4 / 6 small molecule targeted drug composition and the application thereof, the compatibility is reasonable, the medicine sensitivity of the EGFR small molecule inhibitor can be improved and the effect of the CDK4 / 6 small molecule inhibitor in the aspect of colorectal tumor resistance can be further exerted by the combination of the EGFR small molecule inhibitor and the CDK4 / 6 small molecule inhibitor, so that the treatment effect of the EGFR small molecule inhibitor is improved, experiments prove that the combined medication of the EGFR small-molecule inhibitor and the CDK4 / 6 small-molecule inhibitor significantly enhances the inhibition of the activity of colorectal tumor cells compared with the single medication, reduces the single medication dosage, can reduce the drug toxicity, is expected to become a new treatment solution for colorectal cancer with unsatisfactory treatment effect on the EGFR inhibitor, and broad application prospects are achieved.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to the application of the combination of EGFR small-molecule inhibitor Erlotinib and CDK4 / 6 small-molecule inhibitor Palbociclib in inhibiting the growth of tumor cells, especially the application in the preparation of drugs for inhibiting the growth of colorectal cancer cells . Background technique [0002] According to the latest global cancer report released by the American Cancer Society in 2020, colorectal cancer ranks third in terms of incidence and mortality, which shows its danger. In my country, the incidence of colorectal cancer accounts for 38.8% of all malignant tumors, with about 225,000 new cases in men and 163,000 new cases in women every year. With the progress of the times and the improvement of dietary structure, the incidence and mortality of colorectal cancer are increasing year by year, with a growth rate of about 4.2% per year, far exceeding 2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K31/517A61P35/00A61P1/00
CPCA61K31/517A61K31/519A61P1/00A61P35/00A61K2300/00
Inventor 周小晖林凡杨柳贡叶清刘晓蓉
Owner NANJING MEDICAL UNIV
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