Pharmaceutical composition containing USP13 (ubiquitin-specific proteases 13) inhibitor and PARP (poly ADP-ribose polymerase) inhibitor and application thereof

A technology of composition and inhibitor, applied in pharmaceutical composition containing USP13 inhibitor and PARP inhibitor, application field in cancer treatment

Inactive Publication Date: 2017-07-25
SHANGHAI EAST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The emergence of drug resistance limits the clinical use of anticancer drugs such as cisplatin

Method used

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  • Pharmaceutical composition containing USP13 (ubiquitin-specific proteases 13) inhibitor and PARP (poly ADP-ribose polymerase) inhibitor and application thereof
  • Pharmaceutical composition containing USP13 (ubiquitin-specific proteases 13) inhibitor and PARP (poly ADP-ribose polymerase) inhibitor and application thereof
  • Pharmaceutical composition containing USP13 (ubiquitin-specific proteases 13) inhibitor and PARP (poly ADP-ribose polymerase) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Expression of deubiquitinating enzyme USP13 in breast cancer cells

[0144] Detection of USP13 expression in MCF10A normal breast cells and BT20, BT549, HS5787, MDA-MB231, HCC1954, MCF7 breast cancer cells

[0145] The result is as figure 1 Shown: The expression of USP13 was not detected in MCF10A normal breast cells, but the expression of USP13 could be detected in BT20, BT549, HS5787, MDA-MB231, HCC1954, and MCF7 breast cancer cells, and the expression of USP13 in MDA-MB231 cells was the highest . Therefore, in the subsequent examples, MDA-MB231 breast cancer cells were selected as the experimental subjects.

Embodiment 2

[0147] Knockout of USP13 using CRISPR-Cas9 system to study the effect on homologous recombination repair efficiency (HR) and cell growth of tumor cell lines

[0148] In MDA-MB231 breast cancer cells, USP13 was knocked out using CRISPR-Cas9 system. Western results showed that the MDA-MB231 cell line that knocked out USP13 through the CRISPR-Cas9 system had been screened to stably deplete USP13, and the two obtained MDA-MB231 cell lines that stably depleted USP13 were named 231-P1 and 231-P2 ( figure 2 A). Homologous recombination repair efficiency (HR) experiments showed that compared with the control, the repair efficiency of MDA-MB231 breast cancer cells 231-P1 and 231-P2 after depleting USP13 was significantly reduced, only 40-50% of the control. ( figure 2 B).

[0149] Olaparib is a commonly used PARP inhibitor. Olaparib can inhibit the DNA damage repair of tumor cells and promote tumor cell apoptosis. In this example, clone formation experiments were performed on th...

Embodiment 3

[0152] Effects of USP13 inhibitors and PARP inhibitors on homologous recombination repair efficiency (HR) and cell growth in breast cancer cell lines

[0153] In this example, the effects of administration of PARP inhibitor Olaparib and USP13 inhibitor Spautin1 on homologous recombination repair efficiency (HR) and cell growth of breast cancer cell lines were studied.

[0154] Homologous recombination repair efficiency experiments are divided into four groups, including:

[0155] Control group: no drug treatment.

[0156] Control cells treated with Spautin1: the concentration of Spautin1 was 1 μM.

[0157] Subtracted USP13 cell group: no drug treatment.

[0158]Depleted USP13 cells administered Spautin1 group: the concentration of Spautin1 was 1 μM.

[0159] The result is as image 3 As shown in A, compared with the control, the use of USP13 inhibitor Spautin1 can significantly reduce the homologous recombination repair efficiency of breast cancer cells, and the repair eff...

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Abstract

The invention provides a pharmaceutical composition containing a USP13 inhibitor and a PARP inhibitor and application thereof. Specifically, the invention provides a pharmaceutical composition which contains the active constituent (a) USP13 inhibitor, the active constituent (b) PARP inhibitor, and (c) a pharmaceutically acceptable carrier. The USP13 inhibitor can remarkably improve the anti-tumor effect of the PARP inhibitor, and the homologous recombination repair efficiency of tumor cells can be reduced remarkably through combination of the two inhibitors, so that tumor growth can be suppressed more effectively. The pharmaceutical composition can effectively treat cancer.

Description

technical field [0001] The present invention relates to the field of medicine, more specifically to the pharmaceutical composition containing USP13 inhibitor and PARP inhibitor, and the application of said composition in cancer treatment Background technique [0002] Maintaining genome stability is critical to maintaining the proper functioning of various organs in the human body. The body has a set of response mechanisms to deal with DNA damage. Germline mutations in proteins important in the DNA damage response pathway, such as ATM, BRCA1, BRCA2, and Chk2, are associated with cancer susceptibility. These important proteins in the DNA damage response signaling pathway have many feedback regulation and cross-response in the response pathway, making the DNA damage response pathway a complex network system. And this whole network system is precisely regulated by protein post-translational modification. The regulation of post-translational modification of DNA damage proteins...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61P35/00A61K31/517A61K31/502A61K31/4184A61K31/55A61K31/713
CPCA61K45/06A61K31/4184A61K31/502A61K31/517A61K31/55A61K31/713A61K2300/00
Inventor 李昀辉袁健罗坤甜吴晨明尹玉娇李磊陈玉平王艺朵
Owner SHANGHAI EAST HOSPITAL
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