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Anti-tumor glutaminase inhibitor, tumor angiogenesis inhibitor drug compound and application thereof

A tumor angiogenesis and glutaminase technology, applied in the field of biomedicine, can solve the problems of high cost and insignificant effect, and achieve the effect of inhibiting rapid growth, significant synergy and synergy, and significant curative effect

Active Publication Date: 2017-06-27
诺言医药科技(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, drugs such as tumor angiogenesis inhibitors, such as bevacizumab, sorafenib, sunitinib, etc., are expensive and ineffective for a considerable number of patients

Method used

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  • Anti-tumor glutaminase inhibitor, tumor angiogenesis inhibitor drug compound and application thereof
  • Anti-tumor glutaminase inhibitor, tumor angiogenesis inhibitor drug compound and application thereof
  • Anti-tumor glutaminase inhibitor, tumor angiogenesis inhibitor drug compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] [Example 1] Preparation of glutaminase inhibitor compound GI-003 (glutaminase inhibitor-003)

[0096] This example provides a preparation method for glutaminase inhibitor GI-003, the specific steps are:

[0097] (1) Equimolar thiosemicarbazide and ethoxyacetic acid were refluxed at 90° C. for 3 hours under the catalysis of phosphorus oxychloride. The reaction mixture was cooled to room temperature, ice water was added, and the pH was adjusted to 14 with sodium hydroxide. The white precipitate was washed with water. Vacuum dry. It is an intermediate product [1]

[0098]

[0099] 5-(ethoxymethyl)-1,3,4-thiadiazol-2-amine

[0100] (5-(ethoxymethyl)-1,3,4-thiadiazol-2-amine)

[0101] (2) Mix the intermediate product [1] with equal moles of phenylacetyl chloride and pyridine, heat until the mixture is uniform, cool the solution to room temperature, add methanol and filter, leaving a thick solid, which is the intermediate product [2]

[0102]

[0103] N-(5-(hydrox...

Embodiment 2

[0113] [Example 2]: Preparation of glutaminase inhibitor compound GI-006 (glutaminase inhibitor-006)

[0114] This example provides a preparation method for glutaminase inhibitor GI-006, the specific steps are:

[0115] (1) Equimolar thiosemicarbazide and ethoxyacetic acid were refluxed at 90° C. for 3 hours under the catalysis of phosphorus oxychloride. The reaction mixture was cooled to room temperature, ice water was added, and the pH was adjusted to 14 with sodium hydroxide. The white precipitate was washed with water. Vacuum dry. It is an intermediate product [1]

[0116]

[0117] 5-(ethoxymethyl)-1,3,4-thiadiazol-2-amine

[0118] (5-(ethoxymethyl)-1,3,4-thiadiazol-2-amine)

[0119] (2) Mix the intermediate product [1] with equal moles of phenylacetyl chloride and pyridine, heat until the mixture is uniform, cool the solution to room temperature, add methanol and filter, leaving a thick solid, which is the intermediate product [2]

[0120]

[0121] N-(5-(hydro...

Embodiment 3

[0135] [Example 3] Compound GI-003 inhibits the activity of recombinant glutaminase

[0136] The recombinant protein of mouse glutaminase (molecular weight: 66kD) was expressed and prepared in Escherichia coli, and its enzymatic activity was measured after being treated with different concentrations of compound GI-003 or BPTES. The specific steps are as follows: mouse glutaminase was expressed in Escherichia coli using the pET28a plasmid (Novagen: catalog number: 69864-3) cloned with the gene of mouse glutaminase with histidine attached to the N-terminal. The recombinant glutaminase protein is further purified by anion exchange column chromatography. 1 μM glutaminase recombinant protein was mixed with different concentrations of compound GI-003 or the known glutaminase inhibitor BPTES— Warm up to a final volume of 80 μl and spin for 30 minutes. Compound GI-003 or BPTES was diluted with DMSO and the added volume was kept constant (5 μl) in different reactions. Glutamine was ...

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Abstract

The invention relates to an anti-tumor drug compound and application thereof. The compound includes a glutaminase inhibitor and a tumor angiogenesis inhibitor which are used together with each other. The invention especially provides the glutaminase inhibitor as shown as formula (I) listed in a specification. The glutaminase inhibitor has an obvious inhibiting effect for glutaminase activity. The inhibition for the growth of the tumor strain can reach up to 90% or above under the condition that the dosage of the drug combination is only 1 / 5 of the dosage of singly used drugs, the generation of the bloods surrounding human tumors and the transfer of the tumors are obviously restrained and the corresponding side effect of the drug combination is much lower than that of single drug, so that the drug combination of the glutaminase inhibitor and the tumor angiogenesis inhibitor at a certain ratio is effective in treating tumors and the drug combination compared with the single drug has an obvious synergic effect and is an efficient low-toxicity antitumor drug combination.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to the treatment of malignant tumors by combined medicine, in particular to the treatment of malignant tumors by synergistic effects of glutaminase inhibitors and tumor angiogenesis inhibitors. Background technique [0002] Malignant tumor is one of the important chronic diseases that cause human disease and death, and it seriously endangers human health and life safety. In my country, recurrent malignant tumors are mainly lung cancer, gastric cancer, liver cancer, and breast cancer. Traditional treatments for cancer include surgery, radiotherapy, and chemotherapy. In recent years, with the deepening of cell and molecular biology research, the development of drugs for the treatment of malignant tumors, especially the screening of drugs with high efficiency and low toxicity, which specifically target specific signaling pathways or target sites of tumor cells, has attr...

Claims

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Application Information

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IPC IPC(8): A61K31/501A61K31/4439A61K31/506A61P35/00A61P35/02
CPCA61K31/4439A61K31/501A61K31/506
Inventor 侯以琳袁乐洋
Owner 诺言医药科技(上海)有限公司
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