Application of USP9x inhibitor in preparation of medicine for treating osteosarcoma

An inhibitor and osteosarcoma technology, applied in the application field of USP9x inhibitors in the preparation of osteosarcoma drugs, can solve the problems of few clinical application reports, and achieve the effects of avoiding adverse reactions, inhibiting proliferation, and promoting ubiquitination and degradation

Active Publication Date: 2021-01-12
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are few reports on the clinical a...

Method used

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  • Application of USP9x inhibitor in preparation of medicine for treating osteosarcoma
  • Application of USP9x inhibitor in preparation of medicine for treating osteosarcoma
  • Application of USP9x inhibitor in preparation of medicine for treating osteosarcoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1. NGA can inhibit osteosarcoma cell proliferation and promote cell apoptosis.

[0037] Through a series of CCK8 experiments and apoptosis detection screening, we found that NGA can cause obvious proliferation inhibition and apoptosis of osteosarcoma cells U2OS and 143B cells in a time-dependent manner. At the same time, it can effectively inhibit the clone formation ability of tumor cells.

[0038] Experimental process: After treating U2OS, 143B and MG63 cells with different concentrations of NGA for 24h or 48h, the cell proliferation was detected by CCK8 assay, and it was found that NGA could significantly inhibit cell proliferation (see figure 1 ). Then we treated U2OS cells with 0.25, 0.5, 1.0, 1.5, and 2.0 μM NGA for 24 hours, and Western Blot analysis found that NGA could significantly induce cell apoptosis, and the activation of PARP and Caspase3 appeared (see figure 2 A-B), further using AnnexinⅤ-APC and PI double-staining technique, flow cytometry an...

Embodiment 2

[0039] Example 2. NGA effectively promotes the degradation of SOX2, thereby exerting an anti-tumor effect.

[0040] It has been reported in the literature that the high expression of SOX2 effectively promotes the proliferation of tumor cells and the rapid progression of tumors, but according to literature reports, SOX2 can be ubiquitinated by the ubiquitin-conjugating enzyme Ube2s, and then degraded through the proteasome pathway, which also indicates that Therefore, we can regulate the process of tumor growth by regulating the degradation of SOX2. Here we found that NGA can effectively promote the degradation of SOX2 through the proteasome pathway in a time- and concentration-dependent manner without changing its mRNA level, and the proteasome inhibitor MG132 can reverse this phenomenon. Further detection of the ubiquitination level and type of SOX2 by immunoprecipitation found that the ubiquitination level of SOX2 was significantly increased under the influence of NGA, and t...

Embodiment 3

[0042] Example 3. In vivo experiments prove that NGA inhibits the growth of osteosarcoma and at the same time inhibits the expression of SOX2.

[0043] After nude mouse xenograft tumor model, 143B cells were used to conduct tumor formation experiments under the skin of nude mice. When the xenograft tumor grew to a certain extent, 6mg / kg NGA was used for intraperitoneal injection. After 15 days of treatment, compared with the control group, it was found that The size of transplanted tumors formed by mice in the NGA group was significantly smaller than that of the control group, and histochemical results showed that the expression of Ki-67, a proliferation-related indicator, was significantly reduced in the transplanted tumors after treatment, while the number of cells positive for the apoptosis indicator TUNEL was significantly increased, accompanied by SOX2 decrease in expression. This also verifies that NGA can effectively inhibit the process of osteosarcoma in vivo, and at t...

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Abstract

The invention discloses an application of a USP9x inhibitor in preparation of a medicine for treating osteosarcoma. By discovering that the degradation of a proliferation-promoting factor SOX2 can beeffectively promoted by reducing the expression of USP9x or inhibiting the activity of the USP9x in the osteosarcoma, a new target is provided for clinically developing new chemotherapeutic medicinesfor the osteosarcoma; and meanwhile, the research also discovers that NGA can effectively inhibit the deubiquitination enzyme activity of the USP9x, thereby indirectly promoting the ubiquitination degradation of the SOX2, inhibiting the generation and development of tumors, and providing a new molecular structure for clinically discovering new medicines.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to the application of USP9x inhibitors in the preparation of drugs for treating osteosarcoma. Background technique [0002] Osteosarcoma, like sarcoma, is a malignant tumor derived from mesenchyme, named for its immature osteoid. Primary osteosarcoma is mainly seen in children, especially in the period of rapid bone growth - adolescence (10-14 years old), and there are more men than women. Osteosarcoma tends to occur in the metaphysis of the long bones of the extremities, and can also occur in other parts such as the iliac bone and spine. It progresses rapidly, has a high degree of malignancy, is prone to distant metastasis, and has a low long-term survival rate, especially for patients with metastasis. , its 5-year survival rate is about 11%-29%, and 10%-25% of patients clinically diagnosed with osteosarcoma have tumor metastasis, and 90% of them metastasize to t...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/352A61K31/4427A61P35/00
CPCA61K45/00A61K31/352A61K31/4427A61P35/00
Inventor 吴英理顾文莉陈香云雷虎徐含章张星明秦东军杨物鹏
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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