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Application of SMS2 inhibitor in preparation of medicine for treating highly invasive breast cancer

A highly invasive, 1.SMS2 technology, used in drug combinations, antitumor drugs, pharmaceutical formulations, etc., can solve the problem of unproven effects and achieve the effect of inhibiting highly invasive breast cancer

Pending Publication Date: 2021-11-09
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of SMS2 inhibitor can be used to prevent and treat atherosclerosis and inflammatory bowel disease (Y9 in the application of anti-atherosclerosis, Chinese invention patent, application number: 201610392529.1, application date: June 3, 2016; 4 Use of -(2,6-dichlorobenzyloxy)-3-(3-aminopyridine)benzo[d]isoxazole in the preparation of drugs for the prevention and treatment of inflammatory bowel disease, Chinese invention patent, application number: 2019100859357, application date: January 29, 2019), but its effects on macrophages and tumor microenvironment and its role in the prevention and treatment of triple-negative breast cancer in humans and animals have not been experimentally confirmed

Method used

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  • Application of SMS2 inhibitor in preparation of medicine for treating highly invasive breast cancer
  • Application of SMS2 inhibitor in preparation of medicine for treating highly invasive breast cancer
  • Application of SMS2 inhibitor in preparation of medicine for treating highly invasive breast cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: The experimental dose of compound I is effective and safe.

[0047] By measuring the IC of compound I (represented by ComdI in the figure) to mouse-derived macrophage cell line (RAW264.7) and primary bone marrow macrophage cell (BMDM) 50 value, determine the 3-fold half-inhibition rate (IC 50 ) concentration as the experimental dose of the present invention, this dose has significant SMS2 activity inhibitory effect on the same experimental cells (such as figure 1 shown), and the cytotoxic effect at this dose is negligible (as figure 2 Shown), therefore the dosage of compound selected in the present invention is safe and effective.

Embodiment 2

[0048] Example 2: SMS2 is highly expressed in basal-like breast cancer patients, and is positively correlated with the high infiltration of immunosuppressive cells such as M2 macrophages in cancer tissues and the poor prognosis of patients.

[0049] In order to lay the experimental foundation of the present invention, the Oncomine database (https: / / www.oncomine.org) was used to comparatively analyze the expression difference of SMS2 in breast cancer tissue and normal breast tissue; The expression in breast cancer (invisave breast carcinoma) was significantly increased (such as image 3 shown). Next, using the TCGA database (Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumors. Nature 2012; 490:61-70.), the relationship between the expression of SMS2 in 522 cases of human breast cancer and the infiltration of immunosuppressive cells in tumors was analyzed. The mRNA expression of SMS2 in the samples was sorted from high to low, and the tumor samples w...

Embodiment 3

[0051] Example 3: The loss of SMS2 activity can effectively inhibit the M2 polarization of macrophages induced by IL-4

[0052] Isolate the primary bone marrow macrophage BMDM of SMS2 gene knockout mice (KO group), and disperse the cells with 1640 complete medium containing 20ng / mL macrophage colony-stimulating factor (M-CSF) to make the final concentration 2x106 / mL. Cells were plated in 10cm dishes or 12-well plates and cultured for three days. The growth medium was replaced with fresh BMDM on the third day. After the cells were cultured for 7 days, the expression of CD11b and macrophage universal marker protein molecule F4 / 80 was detected by flow cytometry, and the formation of mature BMDM was evaluated (the conditions for inducing differentiation of BMDM in the following examples are the same). Then, the 1640 complete medium containing 20ng / mL interleukin-4 (IL-4, which is a classical macrophage type 2 polarization-inducing factor) was used to induce cell polarization fo...

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Abstract

The invention discloses application of an SMS2 inhibitor in preparation of a medicine for treating highly invasive breast cancer. An overall experiment of establishing a mouse triple negative breast cancer model by utilizing 4T1 cells and an in-vitro experiment performed by adopting mouse primary bone marrow macrophages prove that the compound I serving as an SMS2 specific inhibitor can be used for effectively inhibiting type 2 polarization of macrophages by reducing activity of in-vivo sphingomyelin synthase 2 and sphingomyelin level, the tumor microenvironment is remodeled by reducing the infiltration degree of M2 type macrophages and other bone marrow-derived immunosuppressive cells in the tumor microenvironment of the triple negative breast cancer, so that the in-situ growth of the triple negative breast and the formation and growth of pulmonary metastases caused by menstruation are inhibited. Inhibition of SMS2 activity can be used for preventing and treating highly invasive malignant breast cancer including triple negative breast cancer.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to the application of SMS2 inhibitors in the preparation of medicines for treating highly invasive breast cancer. Background technique [0002] Highly invasive breast cancer is the most lethal type of female breast cancer. Among them, triple-negative breast cancer (Triple-Negative Breast Cancer, TNBC) is the most aggressive subtype of breast cancer, with clinicopathological features of negative estrogen receptor (ER), negative progesterone receptor (PR), Growth factor receptor (HER2) negative, most of the genomics showed basal-like breast cancer characteristics (basal-like breast cancer). TNBC has a high degree of malignancy and common lung and brain metastases. Currently, there is no targeted and effective treatment, and the average survival time of patients is maintained at about 15 months. It is the most lethal subtype of breast cancer (N Engl J Med 2009; 360:790-800 ). For highly inva...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61P35/00
CPCA61K31/4439A61P35/00
Inventor 董继斌余科邓燕叶德泳
Owner FUDAN UNIV
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