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Application of EZH2 (enhancer of zeste homolog 2) inhibitor compounds in preparation of drugs for treating eye melanoma

A melanoma and compound technology, applied in the medical field, can solve the problems of unapplied reports, choroidal melanoma and conjunctival melanoma, and unclear efficacy and mechanism of action, so as to improve the effectiveness of treatment, reduce the enucleation rate, and improve vision prognostic effect

Active Publication Date: 2017-07-21
SHANGHAI NINTH PEOPLES HOSPITAL SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through high-throughput screening of small molecule compound libraries, it can be found that EZH2 small molecule inhibitors are more effective, but so far, there is no report on the application of EZH2 inhibitors in choroidal melanoma, and its effect on choroidal melanoma and conjunctival melanoma Efficacy and mechanism of action are unknown

Method used

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  • Application of EZH2 (enhancer of zeste homolog 2) inhibitor compounds in preparation of drugs for treating eye melanoma
  • Application of EZH2 (enhancer of zeste homolog 2) inhibitor compounds in preparation of drugs for treating eye melanoma
  • Application of EZH2 (enhancer of zeste homolog 2) inhibitor compounds in preparation of drugs for treating eye melanoma

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Experimental program
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Effect test

Embodiment 1

[0019] Immunofluorescence experiment

[0020] Experimental materials: choroidal melanoma tissue chip (Me1004a), purchased from Xi'an Aili Biotechnology Co., Ltd.; H3K27me3 antibody and secondary antibody, purchased from Abcam (Abcam (Shanghai) Trading Co., Ltd.).

[0021] Place the tissue chip in a wet box, and spread PBS on the tissue chip. The diluted H3K27me3 antibody was centrifuged at 13500g for 2min at 4°C. Aspirate the PBS buffer on the glass slide at one end of the tissue chip, and add the antibody from the other end, cover with a humidification box, and incubate at room temperature for 1 h. Wash slides with PBS 3 times (5min / time), add new PBS buffer from one end of the slice, and absorb old buffer from the other end. The diluted secondary antibody was centrifuged at 13500 g for 2 min at 4°C. Add the secondary antibody on the tissue chip, incubate for 1 h at room temperature in a humidified box, and wash the slides 3 times with PBS (5 min / time). Cover the coversli...

Embodiment 2

[0023] Plate colony formation assay

[0024] Experimental materials: Human choroidal melanoma OCM1, OM431 cells, human conjunctival melanoma CRMM1, CM2005.1 cells, 37°C, 5% CO 2 Conventional culture, the medium is DMEM (Gibco) with 10% fetal bovine serum (FBS); GSK503, GSK343, EPZ005687, EPZ-6438 were purchased from MedChemExpress (MCE China); six-well plates were purchased from Thermo Fisher (Thermo Fisher, USA) ; Crystal violet was purchased from Sangong Company (Sangong China);

[0025] OCM1, OM431, CRMM1, and CM2005.1 were cultured to a density of 70%-80%, and the growth state was good. When the refractive index was high, they were digested and centrifuged, and resuspended with 10% FBS DMEM. For cell counting, 1000 cells / well were spread on a six-well plate, and each well of the six-well plate contained 2 ml of 10% DMEM culture medium. After 2 weeks, stain with crystal violet, wash 2 times with PBS, and take pictures to count the number of cell clones. The results are as...

Embodiment 3

[0027] Cell plate clone proliferation assay

[0028] Experimental materials: CCK8 was purchased from Japan Tongren Chemical Co., Ltd.

[0029] OCM1 and CM2005.1 cells were as described above, retinal pigment epithelial cells ARPE-19 and melanocytes PIG-1 were used as normal controls. OCM1, CM2005.1 cells were seeded in 96-well plates, 2000 cells per well, 100ul culture medium, ARPE19 and PIG-1 cells were empty to 4000 cells at 37°C, 5% CO 2 Cultivate, add 10ul CCK8 at 0h, 24h, 48h, and 72h respectively, continue to incubate at 37°C for 4h, measure the absorbance value at OD450nm on the machine, and the results are as follows image 3 shown. EZH2 inhibitor can significantly inhibit the proliferation of retinoblastoma, and the inhibitory effect is enhanced with the increase of concentration. The drug at the same concentration has little toxicity to normal cells.

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Abstract

The invention discloses application of EZH2 (enhancer of zeste homolog 2) inhibitor compounds in the preparation of drugs for treating eye melanoma; the EZH2 inhibitor compounds include GSK503, GSK343, EPZ005687 and EPZ-6438, having molecular formulas of C31H38N6O2, C31H39N7O2, C34H44N4O4 and C32H37N5O3, and molecular structural formulas which are shown in the description. The invention is intended to provide novel targets and drugs for the clinical treatment of eye melanoma, treatment effectiveness is improved, eye ball extraction rate is reduced, vision prognosis of patient is improved, and a novel field is exploited unprecedentedly.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the application of EZH2 inhibitor compounds in the preparation of medicines for treating ocular melanoma. Background technique [0002] Ocular melanoma includes uveal melanoma (Uveal melanoma, UM) and conjunctival melanoma (Conjuctival melanoma, CM). Among them, UM is the intraocular malignant tumor with the highest incidence rate in adults. It originates from the uveal layer and has a high degree of malignancy. The onset of CM is relatively insidious, and it does not affect vision in the early stage. When it is found, it often spreads and metastasizes, which seriously affects the life safety of patients. Therefore, studying the mechanism of ocular melanoma has a very important clinical significance for exploring new targets for early diagnosis and treatment of ocular melanoma, improving the effectiveness of treatment, reducing the rate of enucleation and metastasis, and improving the vi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61K31/5377A61P35/00
CPCA61K31/496A61K31/5377
Inventor 范先群张赫柴佩韦文旭洋葛盛芳贾仁兵
Owner SHANGHAI NINTH PEOPLES HOSPITAL SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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