Application of SHP-2 inhibitor in preparing medicament for targeting proneuronal glioma

A kind of SHP-2, 1. The technology of SHP-2, applied in the field of novel treatment strategies, can solve the problem that the average survival time of glioma patients is less than two years, and achieve a promising clinical application prospect, sensitive treatment response, and low toxicity Effect

Inactive Publication Date: 2019-04-19
RENJI HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even with the combination of many treatment options such as biological immunotherapy, the average survival time of glioma patients is still less than two years

Method used

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  • Application of SHP-2 inhibitor in preparing medicament for targeting proneuronal glioma
  • Application of SHP-2 inhibitor in preparing medicament for targeting proneuronal glioma
  • Application of SHP-2 inhibitor in preparing medicament for targeting proneuronal glioma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Glioma cell lines are more sensitive to SHP099 than control normal glial cells

[0038] (1) SHP-2 inhibitor SHP099 (MCE, HY-100388) has significantly stronger inhibitory effect on the proliferation of U87, LN229, LN18, T98G, LN444 glioma cell lines than normal control glial cells NHA (Normal human astrocytes).

[0039] U87 (ATCC, CVCL_0022, USA), LN229 (ATCC, CVCL_0393, USA), LN18 (ATCC, CVCL_0392, USA), T98G (ATCC, CVCL_0556, USA), LN444 (ATCC, CVCL_3961, USA) glioma cell lines and Normal control glial cells NHA (Normal human astrocytes, #1811, ScienCell Research Laboratories, USA).

[0040] On the first day, the cells in the end-logarithmic growth phase of each strain were taken, and the culture medium was aspirated. Add 2ml of DPBS (Invitrogen, 14190250) to the culture dish and shake gently, then gently suck off the DPBS (be careful not to blow the cells away). After adding 1 ml of 0.25% trypsin (Gibco, 25200-072) to digest at 37° C. for 2 minutes, the d...

Embodiment 2

[0046] Example 2: Preneuronal glioma cell lines are more sensitive to SHP099 than parental control glioma cell lines

[0047] (1) The inhibitory effect of SHP099 on the proliferation of preneuronal glioma cell line (LN444 overexpressing PDGF-A) was significantly stronger than that of parental control cell line LN444.

[0048] 1.1 293T cell packaging lentivirus:

[0049] 293T cells (purchased from ATCC, ATCC number is CRL-3216 TM ) were cultured in DMEM medium: containing 10% fetal bovine serum (Sigma, 12006C), 1% penicillin and streptomycin (Gibco, 15140-122) and DMEM medium (Gibco, 10564011).

[0050] On the first day, the 293T cells in the logarithmic growth phase were taken (the number of cells was about 5×10 6 ), aspirate the culture medium. Add 2ml of DPBS (Invitrogen, 14190250) to the culture dish and shake gently, then gently suck off the DPBS (be careful not to blow the cells away). After adding 1 ml of 0.25% trypsin (Gibco, 25200-072) to digest at 37° C. for 2 min...

Embodiment 3

[0103] Example 3: SHP099 can also specifically induce cell cycle arrest in pre-neuronal cell lines

[0104] On the first day, take Ink4a / Arf at the end of logarithmic growth - / - mAst PDGFRα / PDGF-A and Ink4a / Arf – / – mAst cells, aspirate off medium. Add 2ml of DPBS (Invitrogen, 14190250) to the culture dish and shake gently, then gently suck off the DPBS (be careful not to blow the cells away). After adding 1 ml of 0.25% trypsin (Gibco, 25200-072) to digest at 37° C. for 2 minutes, the digestion was terminated with 10 ml of fresh DMEM medium. Count, spread to 96-well plate (Corning, 3599), the number of cells is 5×10 4 / well and let it grow for 24h.

[0105] After dissolving SHP099 (MCE, HY-100388) into 10mM mother solution with double distilled water, use fresh DMEM medium -- containing 10% fetal bovine serum (Sigma, 12006C), 1% penicillin and streptomycin (Gibco, 15140-122) Diluted with DMEM culture solution (Gibco, 10564011) to a gradient concentration (0, 5, 10 μM) and ...

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Abstract

The invention provides an application of a SHP-2 inhibitor in preparing a medicament for targeting preneuronal glioma. The invention also provides a medicament for treating the preneuronal glioma, which is a preparation prepared by using the SHP-2 inhibitor as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients. The experimental results show that the SHP-2 inhibitor (SHP099) has little toxicity to normal cells, and the inhibitory effect on proliferation and clone formation of proneuronal glioma cell line is significantly stronger than that of a control cell line. SHP099 can also specifically induce cell cycle arrest in proneuronal glioma cell lines. Therefore, when SHP099 is used for inducing cell cycle arrest, TMZ or radiotherapy can becombined to further enhance the therapeutic reactivity of the proneuronal glioma. SHP099 has high blood brain barrier permeability after oral administration, so that the SHP099 has the best drug-forming property which is difficult to achieve by common SHP-2 inhibitors. The invention provides a novel treatment strategy of SHP099 specifically targeting the proneuronal glioma, and has good clinicalapplication prospect.

Description

technical field [0001] The present invention relates to a novel therapeutic strategy targeting preneuronal glioma with SHP099. Background technique [0002] The latest statistics on cancer in China show that the incidence of brain tumors ranks eighth among high-incidence tumors in China, and its death rate ranks ninth. Among them, glioma is the most common primary malignant brain tumor in adults, showing infiltrative growth, difficult to be completely removed by surgery, and has the highest degree of malignancy. The conventional treatment for glioma is postoperative temozolomide (Temozolomide, TMZ) concurrent chemotherapy and radiotherapy plus TMZ adjuvant therapy. However, even with the combination of many treatment options such as biological immunotherapy, the average survival period of glioma patients is still less than two years. Therefore, it is urgent to explore targeted and individualized novel therapeutic drugs based on the molecular mechanism of glioma occurrence ...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K31/4188A61P35/00
CPCA61K31/506A61K31/495A61P35/00A61K2300/00
Inventor 冯海忠张伟伟李彦欣侯艳丽
Owner RENJI HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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