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Application of compound containing allenamide group in preparation of protein inhibitors, protein cross-linkers or protein markers

A technology of allenamide group and allenamide, which is applied in the field of biochemistry, can solve the problems of slow reaction rate between acrylamide and cysteine, affecting selectivity, etc., and achieves strong application value, simple addition product and stable structure Effect

Inactive Publication Date: 2018-06-12
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most electrophilic warheads have more or less defects. For example, α-haloketone and maleimide will react with lysine and histidine to affect the selectivity, and the reaction between acrylamide and cysteine ​​will affect the selectivity. slow reaction rate

Method used

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  • Application of compound containing allenamide group in preparation of protein inhibitors, protein cross-linkers or protein markers
  • Application of compound containing allenamide group in preparation of protein inhibitors, protein cross-linkers or protein markers
  • Application of compound containing allenamide group in preparation of protein inhibitors, protein cross-linkers or protein markers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Synthesis of EGFR covalent inhibitor ACI-1

[0049]

[0050] 3-Butynoic acid (168 mg, 2 mmol) was dissolved in DCM (2.0 mL), and DMF (cat., 16 μL) and oxalyl chloride (203 μL, 2.4 mmol) were gradually added dropwise to the solution at 0°C. The reaction was warmed to room temperature and stirred at room temperature for 2 hours. After the reaction, the solvent and excess oxalyl chloride were removed under reduced pressure, and the resulting residue was redissolved in DCM (4 mL). This solution was then added dropwise to a solution of compound 1-1 (254 mg, 0.8 mmol) and triethylamine (0.84 mL, 6 mmol) in THF / DCM (50 mL / 6 mL) at 0° C. for about 20 minutes. After the reaction was stirred at 0°C for 1 h, the reaction was washed with saturated NaHCO 3 The solution (15 mL) was quenched and the organic phase was collected. The aqueous phase was further extracted with ethyl acetate (30 mL×3). The organic phases were combined and washed with saturated brine (20 mL...

Embodiment 2

[0055] The computer simulation of the combination of EGFR and ACI-1 obtained in Example 1 shows that the distance between the enamide in ACI-1 and the 797-position cysteine ​​in the EGFR binding pocket is relatively close, which provides a basis for the formation of covalent bonds.

[0056] In order to prove that they can indeed form covalent linkages, the EGFR kinase protein was further co-incubated with ACI-1 obtained in Example 1 for 6 hours at 37°C, and at the same time DMSO was used to replace ACI-1 as a negative control, and then the samples were Perform liquid phase tandem mass spectrometry analysis, the results are as follows Image 6 shown. The results showed that the molecular weight of the chymotrypsin hydrolyzed peptide containing cysteine ​​797, the experimental group (ACI-1 treatment) increased the molecular weight of ACI-1 compared with the control group (DMSO treatment). This result proves that ACI-1 can form a covalent binding with EFGR, ACI-1 is a covalent E...

Embodiment 3

[0059] In order to prove the antitumor effect of its EGFR covalent inhibitor ACI-1, the present invention is tested on lung cancer cell line (NCI-H1975), and the results are as follows: Figure 7 shown. Further tests were carried out on the nude mouse model, and the results were as follows Figure 8 shown.

[0060] The experimental results show that ACI-1 has excellent anti-tumor effect, and the effect is significantly better than the existing anti-tumor drug Gefitinib.

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PUM

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Abstract

The invention relates to an application of a compound containing an allenamide group in preparation of protein inhibitors, protein cross-linkers or protein markers. The invention further relates to anepidermal growth factor receptor (EGFR) protein covalent inhibitor and a preparation method thereof. The EGFR protein covalent inhibitor has excellent anti-tumor activity. According to the application, the compound containing the allenamide group can selectively react with a mercapto group of cysteine to form covalent-bond connection, and the specificity of the allenamide group provides a powerful tool for selectively marking the cysteine in future.

Description

technical field [0001] The invention relates to the field of biochemical technology, in particular to the application of compounds containing allenamide groups in the preparation of protein inhibitors, protein cross-linking agents or protein markers. Background technique [0002] Covalent inhibitors, also known as irreversible inhibitors, are a class of inhibitors that exercise their biological functions by forming irreversible covalent bonds with target proteins. Over the past few decades, covalent drugs have been approved as effective treatments for a variety of clinical conditions and have made great contributions to human health. Covalent drugs that have attracted worldwide attention include aspirin, clopidogrel, lansoprazole and esomeprazole. It is precisely because of the historical success of these covalent drugs and the potential advantages of covalent inhibitors, including better biological activity and specificity, prolonged action time, suitable for rational desi...

Claims

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Application Information

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IPC IPC(8): C07D239/94A61K31/517A61P35/00C09K11/06G01N21/64
CPCC07D239/94C09K11/06C09K2211/1044G01N21/6486
Inventor 雷晓光李强董婷
Owner PEKING UNIV
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