WO2014157966A1 - 글리코겐 신타아제 키나아제-3베타 억제물질을 유효성분으로 포함하는 난소과립세포종양의 예방 또는 치료용 약학적 조성물 및 건강기능성식품 조성물 - Google Patents
글리코겐 신타아제 키나아제-3베타 억제물질을 유효성분으로 포함하는 난소과립세포종양의 예방 또는 치료용 약학적 조성물 및 건강기능성식품 조성물 Download PDFInfo
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- WO2014157966A1 WO2014157966A1 PCT/KR2014/002619 KR2014002619W WO2014157966A1 WO 2014157966 A1 WO2014157966 A1 WO 2014157966A1 KR 2014002619 W KR2014002619 W KR 2014002619W WO 2014157966 A1 WO2014157966 A1 WO 2014157966A1
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to a pharmaceutical composition and health functional food composition for the prevention or treatment of ovarian granulocytoma, and more specifically to the prevention or prevention of ovarian granuloma tumor comprising glycogen synthase kinase-3beta inhibitor as an active ingredient.
- the present invention relates to a therapeutic pharmaceutical composition and nutraceutical composition.
- GCT ovarian granule cell tumor
- SCST malignant ovarian stromal tumor
- ovarian granulocytoma is less than 5% of all ovarian cancers and 90% or more patients are diagnosed and treated before 20s, development of a composition effective for the prevention, improvement or treatment of ovarian granuloma tumors very important.
- FOXL2 is known as a winged-helix / forkhead (FH) domain transcription factor, and various studies have been conducted on FOXL2.
- FH winged-helix / forkhead
- FOXL2 mRNA is expressed in ovarian cells and the gradual expression of FOXL2 mRNA, and FOXL2 mRNA is expressed in both immature and mature mouse ovaries from the developmental stage, and is particularly found in small or medium follicles. By confirming limited expression in granulosa cells, it was reported that FOXL2 is a factor regulating the growth of follicles.
- the present invention is a group consisting of a compound represented by the formula (1), a pharmaceutically acceptable salt of the compound represented by the formula (1), a compound represented by the formula (2), and a pharmaceutically acceptable salt of the compound represented by the formula (2) It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of ovarian granulocytic tumors comprising an active ingredient selected from.
- the present invention provides a compound represented by the formula (1), a pharmaceutically acceptable salt of the compound represented by the formula (1), a compound represented by the formula (2), and a pharmaceutically acceptable salt of the compound represented by the formula (2)
- Another object of the present invention is to provide a nutraceutical composition for preventing or improving ovarian granulocytic tumors comprising an active ingredient selected from the group consisting of:
- the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt of the compound represented by the formula (1), a compound described by the formula (2), and a pharmaceutically acceptable compound of the compound represented by the formula (2) It provides a pharmaceutical composition for the prophylaxis or treatment of ovarian granulocytic tumors comprising an active ingredient selected from the group consisting of salts.
- the composition is characterized by inhibiting glycogen synthase kinase-3beta (Glycogen synthase kinase 3-beta; GSK3beta).
- composition is characterized in that it inhibits the phosphorylation of serine (serine), the 33rd amino acid of the forkhead box L2 (FOXL2) protein.
- the present invention provides a compound represented by the formula (1), a pharmaceutically acceptable salt of the compound represented by the formula (1), a compound represented by the formula (2), and a pharmaceutically acceptable salt of the compound represented by the formula (2) It provides a health functional food composition for the prevention or improvement of ovarian granulocytic tumors comprising an active ingredient selected from the group consisting of.
- the composition is characterized by inhibiting glycogen synthase kinase-3beta (Glycogen synthase kinase 3-beta; GSK3beta).
- composition is characterized in that it inhibits the phosphorylation of serine (serine), the 33rd amino acid of the forkhead box L2 (FOXL2) protein.
- the composition according to the present invention is a compound of Formula 1, a pharmaceutically acceptable salt of a compound of Formula 1, a compound of Formula 2 below, and a pharmaceutically acceptable compound of Formula 2 Glycogen synthase kinase 3-beta (GSK3beta) is inhibited by including as an active ingredient selected from the group consisting of possible salts, thereby, the 33rd amino acid of FOXL2 (forkhead box L2) protein Has the effect of inhibiting the phosphorylation of serine (serine) can be usefully used as a composition for the prevention or treatment of ovarian granuloma tumor. In addition, it is expected that it can be usefully used as a nutraceutical composition.
- GSK3beta Glycogen synthase kinase 3-beta
- 1 is a diagram showing the results of nucleotide sequence conservation analysis of S33 residues between mammalian and non-mammalian FOXL2.
- FIG. 2 shows the results of cloning the FOXL2 non-phosphorylated mutant S33A and the hyperphosphorylated mutant S33D mutant by using Western blotting.
- 3 is a view showing the result of predicting the kinase involved in phosphorylation using GPS2.1 phosphoplot.
- Figure 4 shows the results of Western blotting analysis for identifying kinases involved in phosphorylation of FOXL2 S33 residues.
- 5 is a view showing the results of Western blotting analysis to confirm whether GSK3beta specifically involved in the phosphorylation of the residue FOXL2 S33.
- Figure 6 is a view showing the results of Western blotting analysis for confirming the stable overexpression of FOXL2 and S33 specific GSK3beta effect.
- FIG. 7 is a diagram showing the results of immunoprecipitation analysis for identifying binding domains of GSK3beta and FOXL2 proteins.
- FIG. 8 is a view showing the results of Western blotting analysis to confirm the degree of S33 phosphorylation of FOXL2 C134W (GCT).
- 9 is a graph showing the results of a direct phosphorylation test of FOXL2 C134W and S33 residues.
- FIG. 10 is a diagram showing the results of immunoprecipitation analysis to confirm the degree of GSK3beta binding between the FOXL2 C134W mutation and WT.
- FIG. 11 is a view showing the results of luciferase analysis and cell viability analysis for verifying GSK3beta inhibitory effect.
- FIG. 12 is a diagram showing the results of protein stability experiments for verifying GSK3beta inhibitory effect.
- Figure 13 is a diagram showing the results of cell growth rate experiments for verifying GSK3beta inhibitory effect.
- the present invention relates to 3- (2,4-dichlorophenyl) -4- (1-methyl-1H-indol-3-yl) -1H-pyrrole-2,5-dione ⁇ 3- ( 2,4-Dichlorophenyl) -4- (1-methyl-1H-indol-3-yl) -1H-pyrrole-2,5-dione ⁇ , a pharmaceutically acceptable salt of the compound of Formula 1, N-[(4-methoxyphenyl) methyl] -N '-(5-nitro-thiazol-2-yl) urea described as 2 ⁇ N-[(4-Methoxyphenyl) Methyl] -N'-(5 -nitro-thiazol-2-yl) urea ⁇ , and a pharmaceutical for the prophylaxis or treatment of ovarian granuloma tumors comprising as an active ingredient selected from the group consisting of pharmaceutically acceptable salts of the compounds of formula (2) To provide a composition.
- Each compound represented by Chemical Formula 1 and Chemical Formula 2 may be prepared by a known chemical synthesis method, or a commercial reagent may be purchased and used.
- glycogen synthase kinase 3-beta specifically regulates the phosphorylation of FOXL2 S33 residues (see Example 4), Formula 1
- GSK3beta glycogen synthase kinase 3-beta
- phosphorylation of FOXL2 S33 residues was reduced (see Example 5)
- cell growth rate of C134W mutant which was found in ovarian granuloma cells (GCT) was reduced ( Example 9)
- the size of the tumor induced in ovarian granuloma cells is reduced (see Example 10).
- the compound represented by Formula 1 or Formula 2 may be used in the form of a pharmaceutically acceptable salt, and the term “pharmaceutically acceptable salt” used in the present invention causes severe irritation to the organism to which the compound is administered. It means a form of a compound that does not impair the biological activity and physical properties of the compound.
- Acid addition salts formed with pharmaceutically acceptable free acids are useful.
- Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
- Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
- the acid addition salts according to the present invention are dissolved in conventional methods, for example, compounds of formula (1) or (2) in excess acid aqueous solution, and the salts are water miscible organic solvents, such as methanol, ethanol, acetone. Or by precipitation with acetonitrile. Equivalent amounts of the compounds of formula (1) or (2) and acids or alcohols in water may be heated and then the mixture is evaporated to dryness or the precipitated salts may be produced by suction filtration.
- Bases can also be used to make pharmaceutically acceptable metal salts.
- Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
- Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
- prevention means any action that inhibits or delays the onset of ovarian granuloma by administration of the composition of the present invention.
- treatment refers to any action in which symptoms caused by ovarian granuloma are improved or beneficially altered by administration of the composition of the present invention.
- the pharmaceutical composition according to the present invention is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
- diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
- Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, or the like represented by one or more compounds of the invention. And sucrose, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.
- Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
- non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
- base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
- compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the condition and weight of the patient, Depending on the drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
- composition according to the invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level refers to the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of the drug, and other factors well known in the medical arts.
- the compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
- the effective amount of the compound according to the present invention may vary depending on the age, sex, and weight of the patient, and generally 0.001 to 150 mg, preferably 0.01 to 100 mg daily or every other day or 1 day per kg of body weight It can be administered in 1 to 3 times.
- the dosage may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.
- the present invention provides a pharmaceutical composition of a compound represented by Formula 1, a pharmaceutically acceptable salt of a compound represented by Formula 1, a compound represented by Formula 2, and a compound represented by Formula 2 It provides a health functional food composition for the prevention or improvement of ovarian granulocytic tumor comprising an active ingredient selected from the group consisting of acceptable salts. That is, the composition of the present invention may be used simultaneously or separately with a medicament for the treatment of tumors before or after the onset of ovarian granuloma for the prevention or improvement of ovarian granuloma.
- the term “improvement” refers to any action that at least reduces the parameters associated with the condition being treated, such as the extent of symptoms.
- the dietary supplement composition according to the present invention inhibits glycogen synthase kinase 3-beta (GSK3beta), and thus, the 33rd amino acid of FOXL2 (forkhead box L2) protein is serine (serine). Because it inhibits the phosphorylation of), it can be added to dietary supplements such as foods and beverages for the purpose of preventing or improving ovarian granuloma tumors.
- GSK3beta glycogen synthase kinase 3-beta
- Examples of foods to which the above-mentioned substances may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and the like includes all the health functional foods in the conventional sense.
- composition of the present invention may be added as it is to food or used with other food or food ingredients, and may be appropriately used according to conventional methods.
- the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
- the compositions of the invention are added in an amount of up to 15% by weight, preferably up to 10% by weight relative to the raw materials.
- the amount may be below the above range.
- composition for health drinks of the present invention is not particularly limited to other ingredients except for containing the compound as essential ingredients in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
- natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- natural flavoring agents such as, tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
- the proportion of the natural carbohydrate can be appropriately determined by the choice of those skilled in the art.
- the composition for health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, colorants and neutralizing agents (cheese, chocolate, etc.), pectic acid and salts thereof , Alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
- the composition of the present invention may contain fruit flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives may also be appropriately selected by those skilled in the art.
- KGN Human granulosa cells
- constructs of FOXL2 WT wild type
- S33D wild type
- S33A wild type
- C134W C134W
- NP-40 Nonidet P-40
- Bicinchoninic acid (BCA) TM protein assay was performed. Quantified protein was electrophoresed using SDS-PAGE method and transferred to PVDF (polyvinylidene fluoride) membrane and incubated with each antibody to be confirmed. Secondary antibodies were then identified using the ChemDoc machine.
- Cells were sampled and lysed in NP-40 lysis buffer to quantify protein levels. Thereafter, the antibody of the specific protein to be precipitated and the normal IgG of the antibody which is a control group were independently cultured together with the proteinase agrose G which binds to the antibody. The cultured samples and beads were washed three times with NP-40 buffer, and the samples were loaded using Western blotting. Then, the bands were identified by antibodies of other proteins to see the binding.
- the overexpressed samples were incubated with 50 ⁇ M of proteosome inhibitor MG132 and sampled with NP-40 buffer. Thereafter, the overexpressed protein was precipitated using immunoprecipitation, and the sample was loaded using western blotting to incubate with ubiquitine antibodies and SUMO antibodies, and the bands were identified by a chemdoc machine.
- the band of the FOXL2 S33 residue was not identified, and the hyperphosphorylation mutation was confirmed by confirming the band darker than the wild type (WT).
- glycogen synthase kinase-3 beta (Glycogen synthase kinase; GSK3beta) was confirmed to represent 9.75. Therefore, from the above results, it could be predicted that the kinase could be involved in phosphorylation of FOXL2 S33 residues.
- GSK3beta inhibitor SB 216763
- RSK inhibitor S0101
- ERK inhibitor U0126
- JNK inhibitor SP600125
- AKT inhibitor LY 294002
- the FOXL2 WT wild type was overexpressed in KGN cells, and then treated with 10 ⁇ M of each kinase inhibitor. After 18 hours of incubation, the cells were sampled and Western blotting was performed to measure phosphorylation change. At this time, the phosphorylation change was measured using an antibody that specifically binds to the peptide consisting of the amino acid of SEQ ID NO: 21, the results are shown in FIG.
- AR-A014418 includes a compound represented by the formula (2).
- KGN cells which are ovarian granule cells, were sampled and immunoprecipitation was used to confirm the binding of FOXL2 and GSK3beta proteins.
- the binding of FOXL2 with a mutant mutant protein (1-94 aa, 1-218 aa, 218-376 aa deletion forkhead domina) was confirmed using immunoprecipitation. Is shown in FIG. 7.
- FOXL2 and GSK3beta proteins directly bind to each other and could be confirmed to bind to the N-terminal domain.
- Luciferase analysis and cell viability analysis of FOXL2 target genes TNFR1, FAS, Caspase 8 and p21 proteins were performed to verify the effects of GSK3beta inhibition that regulates phosphorylation of FOXL2.
- luciferase assays were performed using 170 ng of pCMV-galactosidase plasmid DNA, 300 ng of TNFR1, FAS, Caspase 8, p21 of reporter DNA, FOXL2 or mutant protein plasmid in 6 wells of 4 ⁇ 10 5 cells per well. After transfection using Microporator MP-100, and cultured for 20 hours, the absorbance was measured using a PerferElmer 1420 counter using a Luciferase kit provided by Promega, and the results are shown in FIG. 11.
- cell viability assay was performed after overexpressing plasmids expressing specific proteins as 2 ⁇ 10 4 KGN cells in 96 wells. Afterwards, cell viability was measured by a PerkinElmer 1420 counter using a CellTiterGlo cell viability kit provided by Promega, and the results are shown in FIG. 11.
- 6-week-old mature male BALB / c-nu mice were purchased from Central Experimental Animal Co., Ltd. .
- Five animals were housed in polycarbonate and freely supplied with solid feed and drink for laboratory animals. Temperature, humidity, ventilation frequency, lighting time, and illumination were induced constantly in the breeding laboratory environment.
- Tumors were induced by subcutaneous injection of 3 ⁇ 10 7 mice into KGN cells stably expressing FOXL2. After 3 weeks of injection, GSK3beta inhibitor (AR-A014418) was directly injected into the tumor-induced portion 10 times for 2 weeks at 2 mg / kg, and the tumor size was measured. The results are shown in FIG. 14.
- GSK3beta inhibitors can substantially inhibit tumor production of ovarian granule cells in vivo.
- the GSK3beta inhibitor has an excellent effect on the prevention or treatment of ovarian granulocytoma.
- composition according to the present invention inhibits glycogen synthase kinase 3-beta (GSK3beta) and has the effect of inhibiting phosphorylation of serine, the 33rd amino acid of the forkhead box L2 protein. It can be usefully used as a composition for preventing or treating ovarian granuloma.
- GSK3beta glycogen synthase kinase 3-beta
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Abstract
Description
돌연 변이형 | Forward primer(5'→3') | Reverse primer(5'→3') | ||
FOXL2 | 서열번호 1 | CTAGAATTCAAATGATGGCCAGCTACCCC | 서열번호 2 | CTACTCGAGTCAGAGATCGAGGCGCGAATG |
S33A | 서열번호 3 | CCGGCCCCAGGCAAGGGCGGTGGGGGT | 서열번호 4 | ACCCCCACCGCCCTTGCCTGGGGCCGG |
S33D | 서열번호 5 | CCGCCGGATCCAGGCAAGGGCGGT | 서열번호 6 | ACCGCCCTTGCCTGGATCCGGCGG |
S263A | 서열번호 7 | CAGGCCATGGCGCTGCCCCCCGGC | 서열번호 8 | GCCGGGGGGCAGCGCCATGGCCTG |
K25R | 서열번호 9 | GGTCGCACAGTCAGAGAGCCAGAA | 서열번호 10 | TTCTGGCTCTCTGACTGTGCGACC |
K36R | 서열번호 11 | CCAGGCAGAGGCGGTGGGGGTGGC | 서열번호 12 | GCCACCCCCACCGCCTCTGCCTGG |
K48R | 서열번호 13 | GCCCCGGAGAGACCGGACCCG | 서열번호 14 | CGGGTCCGGTCTCTCCGGGGC |
K54R | 서열번호 15 | CCGGACCCGGCGCAGAGACCC | 서열번호 16 | GGGTCTCTGCGCCGGGTCCGG |
K87R | 서열번호 17 | ATCATCGCGAGATTCCCGTTC | 서열번호 18 | GAACGGGAATCTCGCGATGAT |
C134W | 서열번호 19 | GCCTGGGAAGACATGTTCGA | 서열번호 20 | ATGTCTTCCCAGGCCGGGTC |
Claims (12)
- 제1항에 있어서,상기 조성물은 글리코겐 신타아제 키나아제-3베타(Glycogen synthase kinase 3-beta; GSK3beta)를 억제하는 것을 특징으로 하는, 약학적 조성물.
- 제1항 또는 제2항에 있어서,상기 조성물은 FOXL2(forkhead box L2) 단백질의 33번째 아미노산인 세린(serine)의 인산화를 억제하는 것을 특징으로 하는, 약학적 조성물.
- 제4항에 있어서,상기 조성물은 글리코겐 신타아제 키나아제-3베타(Glycogen synthase kinase 3-beta; GSK3beta)를 억제하는 것을 특징으로 하는, 건강기능식품 조성물.
- 제4항 또는 제5항에 있어서,상기 조성물은 FOXL2(forkhead box L2) 단백질의 33번째 아미노산인 세린(serine)의 인산화를 억제하는 것을 특징으로 하는, 건강기능식품 조성물.
- 제7항에 있어서,상기 조성물은 글리코겐 신타아제 키나아제-3베타(Glycogen synthase kinase 3-beta; GSK3beta)를 억제하는 것을 특징으로 하는, 방법.
- 제7항 또는 제8항에 있어서,상기 조성물은 FOXL2(forkhead box L2) 단백질의 33번째 아미노산인 세린(serine)의 인산화를 억제하는 것을 특징으로 하는, 방법.
- 제10항에 있어서,상기 조성물은 글리코겐 신타아제 키나아제-3베타(Glycogen synthase kinase 3-beta; GSK3beta)를 억제하는 것을 특징으로 하는, 사용.
- 제10항 또는 제11항에 있어서,상기 조성물은 FOXL2(forkhead box L2) 단백질의 33번째 아미노산인 세린(serine)의 인산화를 억제하는 것을 특징으로 하는, 사용.
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JP2016505403A JP5973108B2 (ja) | 2013-03-29 | 2014-03-27 | グリコーゲンシンターゼキナーゼ3β抑制物質を有効成分として含む卵巣顆粒細胞腫瘍の予防または治療用の薬学的組成物および健康機能性食品の組成物 |
EP14772608.7A EP2979696B1 (en) | 2013-03-29 | 2014-03-27 | Pharmaceutical composition for preventing or treating ovary granulosa cell tumors containing glycogen synthase kinase-3 beta inhibitor as active ingredient, and functional health food composition |
US14/779,817 US20160058738A1 (en) | 2013-03-29 | 2014-03-27 | Pharmaceutical composition for preventing or treating ovary granulosa cell tumors containing glycogen synthase kinase-3 beta inhibitor as active ingredient, and functional health food composition |
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KR10-2013-0034672 | 2013-03-29 | ||
KR1020130034672A KR101440724B1 (ko) | 2013-03-29 | 2013-03-29 | 글리코겐 신타아제 키나아제-3베타 억제물질을 유효성분으로 포함하는 난소과립세포종양의 예방 또는 치료용 약학적 조성물 및 건강기능성식품 조성물 |
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EP (1) | EP2979696B1 (ko) |
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WO (1) | WO2014157966A1 (ko) |
Citations (3)
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US20020052397A1 (en) * | 2000-07-27 | 2002-05-02 | Leyi Gong | 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of glycogen synthase kinase-3beta |
WO2010040204A1 (en) * | 2008-10-09 | 2010-04-15 | British Columbia Cancer Agency Branch | Detection of granulosa-cell tumors |
US20130071495A1 (en) * | 2010-03-16 | 2013-03-21 | Helmholtz Zentrum Muenchen Deutsches Forschungszentrum fuer Gesundheit und Umwelt (GmbH | Inhibitors of glycogen synthase kinase 3 for use in therapeutic methods and screening method relating thereto |
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US7507547B2 (en) * | 2004-09-09 | 2009-03-24 | University Of Massachusetts | Screening assays for antioxidants and antiproliferative compounds |
WO2006034207A2 (en) * | 2004-09-17 | 2006-03-30 | Vanderbilt University | Use of gsk3 inhibitors in combination with radiation therapies |
US20060121040A1 (en) * | 2004-12-08 | 2006-06-08 | Wisconsin Alumni Research Foundation | Compositions and methods for treating neuroendocrine tumors |
WO2012135588A2 (en) * | 2011-04-01 | 2012-10-04 | Sloan Kettering Institute For Cancer Research | Methods of treating serosal cancer |
CN102258783A (zh) * | 2011-07-14 | 2011-11-30 | 吴效科 | Gsk3抑制剂在制备治疗高雄激素血症药物中的用途 |
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Patent Citations (4)
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US20020052397A1 (en) * | 2000-07-27 | 2002-05-02 | Leyi Gong | 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of glycogen synthase kinase-3beta |
WO2010040204A1 (en) * | 2008-10-09 | 2010-04-15 | British Columbia Cancer Agency Branch | Detection of granulosa-cell tumors |
US20110195070A1 (en) | 2008-10-09 | 2011-08-11 | British Columbia Cancer Agency Branch | Detection of granulosa-cell tumors |
US20130071495A1 (en) * | 2010-03-16 | 2013-03-21 | Helmholtz Zentrum Muenchen Deutsches Forschungszentrum fuer Gesundheit und Umwelt (GmbH | Inhibitors of glycogen synthase kinase 3 for use in therapeutic methods and screening method relating thereto |
Non-Patent Citations (2)
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NEW ENGLAND JOURNAL OF MEDICINE, June 2009 (2009-06-01) |
S. UZBEKOVA ET AL.: "Glycogen synthase kinase 3B in bovine oocytes and granulosa cells: possible involvement in meiosis during in vitro maturation", REPRODUCTION, vol. 138, 2009, pages 235 - 246, XP055285131 * |
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JP2016520541A (ja) | 2016-07-14 |
EP2979696A1 (en) | 2016-02-03 |
US20160058738A1 (en) | 2016-03-03 |
KR101440724B1 (ko) | 2014-09-18 |
EP2979696A4 (en) | 2017-01-04 |
JP5973108B2 (ja) | 2016-08-23 |
EP2979696B1 (en) | 2019-05-08 |
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