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A small molecule inhibitor targeting the combination of EGFR and EPS8 and its application

A small-molecule inhibitor and targeting technology, applied in the small-molecule inhibitor EE02 and its application fields, can solve the problems such as the vacancy of small-molecule inhibitors, and achieve the effects of good clinical applicability, good stability, and simple process production

Active Publication Date: 2020-02-07
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is still a lack of small-molecule inhibitors that specifically block the binding of EPS8 to EGFR by targeting the proximal membrane region of EGFR in the domestic and foreign markets.

Method used

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  • A small molecule inhibitor targeting the combination of EGFR and EPS8 and its application
  • A small molecule inhibitor targeting the combination of EGFR and EPS8 and its application
  • A small molecule inhibitor targeting the combination of EGFR and EPS8 and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Synthesis of Small Molecule Inhibitor EE02

[0060] Through computer-aided drug design (Computer Aided Drug Design, CADD) technology, using SYBYL software virtual docking to screen out a small molecule inhibitor targeting the combination of EGFR and EPS8, named EE02. The molecular formula of the small molecule inhibitor EE02 is: C 44 h 54 N 4 o 6 S, molecular weight: 767, English name: 1-{4-[4-(2-hydroxy-3-{4-[(2Z)-3-phenylprop-2-en-1-yl]piperazin-1- yl}propoxy)benzonesulfonyl]phenoxy}-3-{4-[(2Z)-3-phenylprop-2-en-1-yl]piperazin-1-yl}propan-2-ol, the molecular structure is as follows figure 1 shown. Through conformational analysis, it is found that EE02 is completely docked in the membrane-adjacent region of EGFR and the groove at the junction of the membrane-proximal region and the kinase region, and generates one hydrogen each with Ser at position 671, Asn at position 676 and Arg at position 807 of the EGFR peptide chain bond, a total of 3 hydrogen bo...

Embodiment 2

[0074] Example 2 Small molecule inhibitor EE02 on human lung cancer cell lines A549 and H460 with high expression of EGFR and EPS8, human breast cancer cell line MDA-MB-468 and breast cancer cell line MCF with low / no expression of EGFR but high expression of EPS8 Proliferation inhibitory activity of -7.

[0075] Human lung cancer cell lines A549 and H460 with high expression of EGFR and EPS8, human breast cancer cell line MDA-MB-468 and breast cancer cell line MCF-7 with low / no expression of EGFR but high expression of EPS8 were selected (the cell lines were all purchased from American Type Culture Collection (ATCC). Take cells in the logarithmic growth phase, inoculate 5000 cells / well in a 96-well culture plate, 90 μL per well, and use high-glucose DMEM complete medium containing 10% fetal bovine serum as the medium; after adhering overnight, add final concentrations of 0, 1, 2.5, 5.0, 7.5, 10 μmol / L small molecule inhibitor EE02, placed at 37°C, 5% CO 2 After culturing in ...

Embodiment 3

[0078] Example 3 Small molecule inhibitor EE02 inhibits the proliferation of peripheral blood mononuclear cells in healthy volunteers

[0079] Peripheral blood was collected from 5 healthy volunteers, and peripheral blood mononuclear cells (PBMC) were separated by Ficol density gradient centrifugation, resuspended in culture medium, counted, and plated. Cells were inoculated into 96-well culture plates at 20,000 cells / well, 90 μL per well, and the culture medium was RMPI-1640 complete medium containing 10% fetal bovine serum; after overnight, the final concentrations were 0 , 1, 2.5, 5.0, 7.5, 10 μmol / L small molecule inhibitor EE02, placed at 37°C, 5% CO 2 After culturing in the incubator for 24 hours, add 10 μl cck8 reagent to each well, react for 3 hours, measure the OD value at a wavelength of 450 nm, and calculate the inhibition rate.

[0080] Inhibition rate calculation formula: cell viability = [(OD 实验组 -OD 空白组 )] / [(OD 阴性组 -OD 空白组 )] × 100%. For the inhibitory act...

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Abstract

The invention discloses a small molecular inhibitor EE02 realizing targeted combination of EGFR and EPS8 and application thereof. The small molecular inhibitor has a molecular formula of C44H54N4O6S,the molecular weight being 767, and the Chinese name of 1-{4-[4-(2-hydroxyl-3-{4-[(2Z)-3-phenylpropyl-2-alkene-1-yl]piperazidine-1-yl}propoxyl)phenylsulfonyl]phenoxyl}-3-{4-[(2Z)-3-phenylpropyl-2-alkene-1-yl]piperazidine-1-yl}-2-propanol. The small molecular inhibitor can effectively inhibit the multiplication of EGFR and EPS8 positive tumor, can be used for preparing medicine for treating EGFR and EPS8 positive tumor, and has great potential of being developed into anti-tumor small molecular targeted medicine.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a small molecule inhibitor EE02 targeting the combination of EGFR and EPS8 and its application. Background technique [0002] Epidermal growth factor receptor (EGFR) is a kind of transmembrane glycoprotein receptor superfamily with protein tyrosine kinase (protein tyrosine kinase, PTK) activity, including extracellular region, transmembrane region and cell The inner region (divided into three subregions including the membrane-proximal region, the kinase region, and the C-terminal region), with the extracellular region as the ligand-binding site, and the kinase region as its main functional region[1,2]. EGFR is overexpressed in various tumor cells such as breast cancer, lung cancer, colorectal cancer, and cervical cancer, and is closely related to the occurrence and development of tumors [3,4,5]. [0003] Epidermal Growth Factor Receptor pathway substrate ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/088A61K31/496A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D295/088
Inventor 李玉华李梅芳贺艳杰胡宇行
Owner SOUTHERN MEDICAL UNIVERSITY
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