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Application of small molecule in preparation of mutant type uveal melanoma drug

A melanoma and mutant technology, applied in the field of medical drugs, can solve the problems of difficult to process clinical production and complex molecular structure, and achieve the effects of simple structure, high specific lethality and mature application.

Active Publication Date: 2021-04-09
SHANGHAI NINTH PEOPLES HOSPITAL SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the complex molecular structure of these two natural product compounds, it is difficult to carry out process production and enter the clinic

Method used

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  • Application of small molecule in preparation of mutant type uveal melanoma drug
  • Application of small molecule in preparation of mutant type uveal melanoma drug
  • Application of small molecule in preparation of mutant type uveal melanoma drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] (1) Ilismol can effectively kill GNAQ / 11 mutant UM cells, and knocking down GNAQ reduces the killing effect

[0023] Using high-throughput drug screening (HTS) technology, 7 UM cell lines with different genetic backgrounds were screened for the drug efficacy of 3541 compounds. The ratio of the number of survival cells in the treatment group to the number of survival cells in the control group was set as FC, log 2 FC figure 1 .A, B). Using CCK8 assay, it was found that three GNAQ / 11 mutant cell lines, 92.1, OMM2.3, and OMM1, had IC 50 16.1nM, 22.1nM, and 26nM, respectively, and the three strains of GNAQ / 11 wild-type cell lines Mel285, Mel290, and MUM2B were resistant to the drug ( figure 1 .C,D). Using siRNA to knock down GNAQ in OMM2.3 cells ( figure 1 .E), the knockdown efficiency reached more than 50% ( figure 1 .F), CCK8 assay was used to detect the IC of Ilisimo on OMM2.3 cells 50 , found that after knocking down GNAQ, IC 50 From 0.024uM to 0.124~0.210uM (pf...

Embodiment 2

[0026] (2) Ilismol inhibits the proliferation of GNAQ / 11 mutant UM cells and blocks the cell cycle to G1 phase

[0027] Plate cloning experiments showed that as the concentration of ilismol increased, the killing effect on GNAQ / 11 mutant UM cells was enhanced, and the cell clones could be killed to less than 50% at 20nM ( figure 2 .A, B). The soft agar colony formation experiment also confirmed that ilismol can reduce the tumorigenic ability of UM cells in vitro ( figure 2 .C,D). Flow cytometry proved that ilismol can arrest UM cells in G1 phase and reduce S phase, and WB experiment verified that ilismol can down-regulate the expression of cycle-related proteins c-Myc and Cyclin D1 ( figure 2 .E, F, G).

[0028] The above research results indicate that ilismol can inhibit the proliferation ability of GNAQ / 11 mutant UM cells in vitro, and arrest the cells in the G1 phase by regulating the cycle-related proteins c-Myc and Cyclin D1.

Embodiment 3

[0030] (3) Ilismol can inhibit the proliferation and metastasis of GNAQ / 11 mutant UM cells in zebrafish

[0031] A xenograft tumor model was constructed using Tg(kdrl:egfp) transgenic zebrafish, which labeled vascular endothelial cells with green fluorescence, and systemic vascular distribution could be observed, and GNAQ / 11 mutant UM cells were labeled with the red dye CM-DIL The cell membrane of 92.1 makes it glow red fluorescence. The cells are injected into the yolk sac of 2-day-old zebrafish with a microinjection needle, so that tumors can form in the yolk sac and can be transferred to the eyes, living vessels, Tail and other body organs, the model can be observed up to 8dpf ( image 3 .A). Add different concentrations of ilismol to the culture dish of 3dpf fish eggs, change the liquid every 2 days, observe 8dpf, count the survival rate of fish eggs to calculate the safe concentration, and the survival ratio > 80% is recorded as safe ( image 3 .B). The fish eggs after...

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Abstract

The invention provides application of a small molecule in preparation of a mutant type uveal melanoma drug. The small molecule is elesclomol, and the mutant type uveal melanoma comprises GNAQ or GNA11 mutant type uveal melanoma. The small molecule elesclomol aims at the GNAQ / GNA11 mutant type uveal melanoma, can effectively kill mutant type UM cells, effectively inhibit proliferation of the mutant type UM cells, block the cell cycle to the G1 stage, can well inhibit proliferation and transfer of the GNAQ / GNA11 mutant type UM cells in vivo, and has a poor killing effect on wild type UM cells, thereby showing a specific killing effect on the GNAQ / GNA11 mutant type UM cells. The drug effect of the elesclomol is increased with the increase of the concentration, and the molecular structural formula of the elesclomol is shown as the formula (I) seeing the description.

Description

technical field [0001] The invention belongs to the technical field of medical drugs, and in particular relates to the application of a small molecule in the preparation of mutant uveal melanoma drugs. Background technique [0002] Uveal melanoma (uveal melanoma, UM) is the most common intraocular malignancy in adults, accounting for 5% of systemic melanoma. About 50% of UM metastasize during disease progression, and the most common metastases are liver, accounting for about 90%, followed by lung and bone. The median progression-free survival and overall survival of patients with liver metastases were only 3.3 months and 10.2 months, respectively. Although local treatments such as scleral patch radiotherapy, transpupillary hyperthermia, or enucleation surgery can control primary UM, due to the lack of effective chemotherapeutic drugs, the high transfer rate and mortality of UM are still clinical problems that need to be solved urgently. [0003] The molecular mechanism of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/165A61P35/00A61P35/04
CPCA61K31/165A61P35/00A61P35/04
Inventor 范先群贾仁兵李甬芸张建明李云齐葛盛芳
Owner SHANGHAI NINTH PEOPLES HOSPITAL SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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