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Chemical inhibitor of p53-snail binding and pharmaceutical composition for treating cancer disease containing same as its active ingredient

a technology of p53snail binding and pharmaceutical composition, which is applied in the direction of drug compositions, ester active ingredients, amide active ingredients, etc., can solve the problems of prolonging life span, less than 10%, and low survival rate of lung and pancreatic cancer, so as to improve the survival rate of caner patients or treatment efficiency, the effect of effective treatment or preventing a k-ras mutant cancer

Inactive Publication Date: 2012-01-19
PUSAN NAT UNIV IND UNIV COOPERATION FOUND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]A method of screening a therapeutic agent for K-Ras mutant cancer according to the present invention enables a drug for inhibiting Snail-p53 binding to be specifically screened, thereby effectively treating or preventing a K-Ras mutant cancer, such as pancreatic, lung, cholangiocarcinoma, and colon cancer, of which diagnosis or treatment is not easy.
[0019]Also, a DNA binding domain of p53 is used as a carrier to deliver drug specifically to K-Ras mutant cells, which is very useful for treatment of K-Ras mutant cancer. In addition, K-Ras mutant cancer may be early diagnosed through identification of expression of Snail autoantibody. Thus, it is possible to early diagnose pancreatic cancer of which diagnosis is difficult, thereby increasing a survival rate of caner patients or treatment efficiency.

Problems solved by technology

However, some kinds of cancer including lung and pancreatic cancer still show extremely low survival rate, less than 10%.
Currently available drugs for treating lung and pancreatic cancer have relatively weak effect on extension of life span, and cause various adverse effects.

Method used

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  • Chemical inhibitor of p53-snail binding and pharmaceutical composition for treating cancer disease containing same as its active ingredient
  • Chemical inhibitor of p53-snail binding and pharmaceutical composition for treating cancer disease containing same as its active ingredient
  • Chemical inhibitor of p53-snail binding and pharmaceutical composition for treating cancer disease containing same as its active ingredient

Examples

Experimental program
Comparison scheme
Effect test

example 6

[0126]1. Behaviors of Extracellular p53 and Snail

[0127]1) Tissue Analysis

[0128]Normal and tumor paired cholangioma and liver tissues were obtained from Shunchunhyang Medical Center. Tissues were rapidly frozen in the deep freezer until use. Frozen tissues were sliced and 0.5 mg of tissues was incubated in 0.25 ml serum free medium for 30 min. at 37° C. to allow the release of tissue fluid. After incubation, the culture medium was collected and precipitated with 0.5 ml 100% Et-OH. Precipitated materials were dissolved using RIPA and used for SDS-PAGE and WB analysis. We also obtained same culture medium through the same method and used the culture medium to detect p53 antibody.

[0129]2) p53 ELISA Assay

[0130]To examine the p53, we performed the ELISA following manufacture's protocol (Assay Design). In brief, 0.2 ml tissue cultured media was added to wells and incubated with detection antibody. After washing with a wash buffer, 0.2 ml of a substrate sol and 0.05 ml of a stop solution we...

example 1

1-1. Synthesis of 2-methylthio-1,4-naphthoquinone (1a)

[0143]0.617 mM 1,4-naphtoquinone was dissolved in 30 ml of methanol in 100 ml one-neck round flask, and 1.54 mM sodium thiomethoxide was added thereto and stirred overnight. 50 ml of saturated sodium chloride solution was added to the reaction mixture, followed by extraction three times with 50 ml of chloroform, and an organic layer was dehydrated with an anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was re-crystallized with methanol to produce 2-methylthio-1,4-naphthoquinone that was yellow crystal.

[0144]Yield: 14.0%, melting point: 185-186° C., 1H-NMR (CDCl3, 400 MHz): δ 8.12-8.07(m, 2H), 7.78-7.70(m, 2H), 6.58(s, 1H), 2.40(s, 3H), m / z 205.1 (M+H)+.

1-2. Synthesis of 2-ethylthio-1,4-naphthoquinone (1b)

[0145]2-ethylthio-1,4-naphthoquinone that was yellow crystal was prepared in the same manner as in Example 1-1, except that ethylmercaptan was used instead of s...

example 2

2-1. Synthesis of 2-methylamino-5,8-dimethoxy-1,4-naphthoquinone (5a)

[0163]0.45 mM 5,8-dimethoxy-1,4-naphthoquinone (4) which had been prepared above was dissolved in 30 ml of methanol in 100 ml one-neck round flask and then, 0.687 mmol methylamine was added thereto and stirred at room temperature for 3 hours 0.64 mM sodium dichromate and 0.18 mM sulfuric acid dissolved in water were slowly dropped to the reaction mixture and stirred at room temperature for 3 minutes. Then, 50 ml of saturated sodium chloride was added to the reaction mixture, followed by extraction three times with 50 ml of chloroform and obtained organic layers were gathered and dehydrated with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was subjected to silicagel column chromatography, thereby producing 2-methylamino-5,8-dimethoxy-1,4-naphthoquinone that was reddish brown. The yield and properties of the synthesized compound are as follows.

[0164]Yield...

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Abstract

Provided are compounds for inhibiting Snail-p53 binding and therapeutic agents for cancer including the compounds as an effective component. The Snail-p53 binding inhibitors induce expression of p53 in K-Ras mutant cell lines, thereby enabling effective treatment or prevention of K-Ras mutant cancer, such as, pancreatic cancer, lung cancer, cholangioma, and colon cancer, of which diagnosis or treatment is not easy.

Description

TECHNICAL FIELD[0001]The present invention is directed to a compound that inhibits Snail-p53 binding to induce expression of p53 so as to be effectively used in treating a K-Ras mutant cancer, such as pancreatic cancer, lung cancer, cholangioma, and colon cancer and a therapeutic agent for cancer including the compound as an effective component.BACKGROUND ART[0002]Improvement of anti-cancer drugs and diagnostic tools has raised 5 years survival rate of overall cancer patients up to 50%. However, some kinds of cancer including lung and pancreatic cancer still show extremely low survival rate, less than 10%. Accordingly, development of early diagnostic methods for these cancers is urgently needed to increase survival rates of the cancer patients. Interestingly, K-Ras is predominant event in such cancer, in particular, in pancreatic cancer of which survival rate is 5% or less.[0003]Oncogenic Ras is known to induce senescence and apoptosis through p53 activation, and formation of an onc...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/495C07D211/16C07C313/24C07C323/22C07C323/62C07C323/41G01N33/566C12N5/09A61K31/451A61K31/165A61K31/10A61K31/192A61K31/216A61P35/00C07D295/192
CPCA61K31/10G01N33/5748C07C317/44A61K31/122A61P35/00A61P43/00C07C323/52C07C2602/10C07C317/24C07C317/32G01N33/574
Inventor PARK, BUM JOONHA, NAM CHULLEE, SUN HYESONG, GYU YONGLEE, JEE HYUN
Owner PUSAN NAT UNIV IND UNIV COOPERATION FOUND
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