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Application of compound for targeted inhibition of CDK7 in preparation of inhibited triple negative breast cancer stem cells

A triple-negative breast cancer, compound technology, applied in the field of biomedicine, can solve the problems of poor triple-negative breast cancer and other problems

Inactive Publication Date: 2020-12-15
FUDAN UNIV SHANGHAI CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] Aiming at the above-mentioned technical problems in the prior art, the present invention provides the use of a compound that targets and inhibits CDK7 in the preparation of stem cells that inhibit triple-negative breast cancer. Technical issues with underperforming

Method used

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  • Application of compound for targeted inhibition of CDK7 in preparation of inhibited triple negative breast cancer stem cells
  • Application of compound for targeted inhibition of CDK7 in preparation of inhibited triple negative breast cancer stem cells
  • Application of compound for targeted inhibition of CDK7 in preparation of inhibited triple negative breast cancer stem cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 THZ1 significantly inhibits the growth of triple-negative breast cancer cells

[0033] We treated different types of breast cancer cells (triple negative: CAL-51, BT549, MDM-MB-231, 468; non-triple negative: MCF7, BCAMP37, T47D, BT474) with THZ1 and found that , THZ1 can significantly inhibit the growth of triple-negative breast cells ( figure 2 ).

Embodiment 2

[0034] Example 2 THZ1 targets CDK1, inhibits the phosphorylation of RNA polymerase II, causes apoptosis, significantly inhibits the expression of damage stress repair proteins, and also inhibits the expression of cell cycle regulatory proteins

[0035] To confirm whether THZ1 can inhibit the phosphorylation of RNA-polyII by covalently binding CDK7. We firstly treated MDA-MB-231 and Cal-51 stem cells with THZ1 respectively, collected the cells, and detected them by western-blot. It was positively correlated with the concentration of THZ1; THZ1 also caused the expression of apoptosis protein caspase-3 ( image 3 A). Similarly, we found that THZ1 can significantly inhibit the expression of DNA damage stress repair-related proteins ( image 3 B) and inhibition of cell cycle checkpoint-associated proteins ( image 3 C).

Embodiment 3

[0036] Example 3 THZ1 inhibits the formation and growth of triple-negative breast cancer stem cell spheres

[0037] We treated MDM-MB-231 cells in a stem growth environment with THZ1, and found that THZ1 could significantly inhibit the formation of stem cell spheres, and there was a significant positive correlation with THZ1 concentration ( Figure 4 A); We treated MDM-MB-231 stem cell spheres with THZ1, and found that THZ1 could significantly inhibit the growth of stem cell spheres, and there was a significant positive correlation with the concentration ( Figure 4 B).

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Abstract

The present invention provides an application of a compound for targeted inhibition of CDK7 in preparation of inhibited triple negative breast cancer stem cells. The compound for targeted inhibition of CDK7 is THZ1. The CDK7 targeting inhibitor THZ1 can specifically inhibit growth and stemness maintenance of the triple negative breast cancer stem cells and in-vivo tumorigenesis and growth of the stem cells. Transcriptome sequencing and subsequent biochemical experiment verifications show that the CDK7-targeting inhibitor THZ1 can specifically regulate and control a tumor stemness Notch-Hes signaling pathway, promote stemness transformation of triple-negative breast cancer stem cell subsets, transform stemness cell subsets into non-stemness cells, cause cycle arrest of the triple-negative breast cancer stem cells, inhibit DNA damage repair, promote cell apoptosis, meanwhile, can also directly cause the apoptosis of the stem cells, can remarkably influence growth of the triple-negative breast cancer stem cells, and meanwhile, can play a synergistic sensibilization function in the radiotherapy of the triple-negative breast cancer stem cells.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a compound targeting and inhibiting CDK7, specifically the use of the compound targeting and inhibiting CDK7 in preparing and inhibiting triple-negative breast cancer stem cells. Background technique [0002] Cancer stem cells (breast cancer stem cells, BCSCs) refer to a subset of tumor cells present in tumor tissues with unlimited self-renewal ability, multi-directional differentiation potential, high tumorigenicity, and resistance to radiotherapy and chemotherapy. The existence of cancer stem cells is the main reason for the failure of tumor recurrence and metastasis, tumor radiotherapy and chemotherapy. Therefore, targeting cancer stem cells is one of the effective strategies for tumor therapy. [0003] Triple negative breast cancer (TNBC) refers to estrogen receptors (estrogen receptor, ER), progesterone receptor (progesterone receptor, PR) and human epidermal growth factor receptor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506A61P35/00
CPCA61K31/506A61P35/00
Inventor 苏锋涛郭小毛陆雪官陈倩倩卞慧芳
Owner FUDAN UNIV SHANGHAI CANCER CENT
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