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Combined product of Bcl-2/Bcl-xL inhibitor and chemotherapeutic drug and application of combined product in prevention and/or treatment of disease

A combined product, bcl-2 technology, used in the field of medicine

Active Publication Date: 2021-02-02
ASCENTAGE PHARMA SUZHOU CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, although there is indeed a demand for combined drug regimens and products targeting different target proteins and / or different signal transduction pathways in the prior art, given the complexity of tumorigenesis mechanisms, the unpredictability of interactions between different drugs, etc. Factors, to find feasible combined drug regimens and products that can bring about better effects than single drugs (reduce single drug dose, reduce single drug side effects, and / or work in a synergistic manner, etc.), still a major challenge in the field of medicine
At the same time, in the practice of cancer treatment, the resistance of tumor cells to single-target drugs is also a difficult problem to be overcome

Method used

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  • Combined product of Bcl-2/Bcl-xL inhibitor and chemotherapeutic drug and application of combined product in prevention and/or treatment of disease
  • Combined product of Bcl-2/Bcl-xL inhibitor and chemotherapeutic drug and application of combined product in prevention and/or treatment of disease
  • Combined product of Bcl-2/Bcl-xL inhibitor and chemotherapeutic drug and application of combined product in prevention and/or treatment of disease

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0381] The present invention is further illustrated below through specific examples and comparative examples, but it should be understood that these examples and comparative examples are only used for more detailed description, and should not be interpreted as being used to limit the present invention in any form. invention.

[0382] The experimental methods for which specific conditions are not indicated in the following examples are usually carried out according to the conventional conditions of this type of reaction, or according to the conditions suggested by the manufacturer.

[0383] The experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art or prepared according to methods similar to those disclosed in the present application unless otherwise specified.

[0384] Synthesis Example: Preparation of Exemplary Compounds of Bcl-2 Selective Inhibitors (Compounds 3, 6 and 13)

...

Embodiment 1

[0423] Example 1: Synergistic antiproliferative effect of compound 6 combined with homoharringtonine

[0424] 【Experiment method】:CellTiter- Luminescent cell viability analysis (CTG assay)

[0425] Use the CellTiter according to the manufacturer's instructions- Luminescence method cell viability detection kit, by quantitative determination of ATP test substance in MV-4-11 (Compound 6 sensitive cell line), OCI-AML-3 (Compound 6 non-sensitive cell line), and SKM-1 (Compound 6 6 non-sensitive cell lines) anti-proliferative effect in three AML / MDS cell lines.

[0426] First, the cells in the logarithmic growth phase are collected, centrifuged, and the cell suspension is counted and diluted to adjust to the required concentration. After mixing, add 90 μL of cell suspension to each well of the 96-well plate. The number of cells per well is 10×10 3 cells at 5% CO 2 , and incubate in a 37°C incubator for 2 hours. Set up more than 3 blank control wells containing only medium (...

Embodiment 2

[0432] The results showed that, compared with the curves of compound 6 and HHT alone, the curve of the combined drug shifted to the left, suggesting that the anti-proliferative effect of compound 6 was enhanced in all AML / MDS cell lines tested. The analysis of combined drug effects showed that the combination index (CI value) was less than 0.1 at multiple combined drug concentrations, indicating that compound 6 combined with HHT had synergistic anti-proliferative effects in all tested AML / MDS cell lines. For the specific CI value and the original dose-effect growth inhibition curve of compound 6 combined with HHT, see figure 1 . Example 2: Synergistic effect of compound 6 and homoharringtonine in inducing apoptosis

[0433] 【Experimental method】: flow cytometry analysis

[0434] Cells were collected 24 hours after compound 6 single drug, HHT single drug, or two drugs in combination, and washed once with phosphate buffered saline (PBS). Cells were stained with Annexin-V and ...

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Abstract

The present invention relates to a combined product. The combined product contains a Bcl-2 / Bcl-xL inhibitor and a chemotherapeutic drug, in particular the Bcl-2 / Bcl-xL inhibitor which has a formula I-A and is in the form of free or pharmaceutically acceptable salt or solvate, and homoharringtonine or active derivatives thereof. The invention also relates to application of the combined product in the preparation of a drug for preventing and / or treating cancer, in particular hematological malignancies, and a method for preventing and / or treating the cancer, in particular the hematological malignancies by using the combined product.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a combination product containing a Bcl-2 / Bcl-xL inhibitor and a chemotherapeutic drug and its use in preventing, delaying its progress and / or treating cancer, especially hematological malignancies. Background technique [0002] Apoptosis, also known as programmed cell death, is a precisely controlled cell death mechanism in organisms. It can orderly eliminate unnecessary or damaged cells in the body, and plays an important role in embryonic development and maintaining cell homeostasis. [0003] The Bcl-2 protein family related to the apoptosis function is considered to play an important role in the regulation of apoptosis, and its protein family members can be divided into two subfamilies according to the structure and function, namely, the anti-apoptotic protein family such as Bcl-2 2. Bcl-xl, Mcl-1, etc., and pro-apoptotic protein families, such as Bak, Bax, Bim, B...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/496A61K31/635A61K31/675A61K31/55A61P35/00A61P35/02
CPCA61K45/06A61K31/496A61K31/635A61K31/675A61K31/55A61P35/00A61P35/02A61K2300/00A61P35/04
Inventor 杨大俊翟一帆方东唐秋琼
Owner ASCENTAGE PHARMA SUZHOU CO LTD
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