US20160193238A1 - HNF4-alpha ANTAGONIST AND USE THEREOF - Google Patents

HNF4-alpha ANTAGONIST AND USE THEREOF Download PDF

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US20160193238A1
US20160193238A1 US14/988,124 US201614988124A US2016193238A1 US 20160193238 A1 US20160193238 A1 US 20160193238A1 US 201614988124 A US201614988124 A US 201614988124A US 2016193238 A1 US2016193238 A1 US 2016193238A1
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hnf4
formula
antagonist
group
cancer
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Yon Hui Kim
Seung Yoon Nam
Hee Seo Park
Hae Ryung Chang
Hae Rim Jung
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NATIONAL CANCER CENTER
National Cancer Center Korea
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National Cancer Center
National Cancer Center Korea
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Priority claimed from KR1020160000813A external-priority patent/KR101758208B1/ko
Assigned to NATIONAL CANCER CENTER reassignment NATIONAL CANCER CENTER ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHANG, HAE RYUNG, JUNG, HAE RIM, KIM, Yon Hui, NAM, SEUNG YOON, PARK, HEE SEO
Publication of US20160193238A1 publication Critical patent/US20160193238A1/en
Priority to US15/464,178 priority Critical patent/US9795586B2/en
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
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    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
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    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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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
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention disclosed herein relates to a hepatocyte nuclear factor 4 alpha (HNF4- ⁇ ) antagonist and a use thereof, and more specifically, to an antagonist which specifically binds to the ligand binding domain of HNF4- ⁇ and inhibits the activity of HNF4- ⁇ , and a composition which includes the HNF4- ⁇ antagonist as an active ingredient and is for preventing and treating gastric cancer.
  • HNF4- ⁇ hepatocyte nuclear factor 4 alpha
  • Hepatocyte nuclear factor 4 alpha is a DNA binding protein which is present in nuclei, abundant in the liver, and known as a transcription factor involved in the control of liver-specific genes. Additionally, HNF4- ⁇ is a transcription factor belonging to a steroid receptor family and activates the HNF1- ⁇ gene. Although it was reported in a previous study that HNF4- ⁇ activates the transcription of a target gene in the non-presence of an exogenous ligand, a later study revealed that a particular fatty acid acyl-CoA activates HNF4- ⁇ , thereby controlling the activity of HNF4- ⁇ by a particular ligand.
  • HNF4- ⁇ indeed controls the expression of the genes associated with lipid transport, such as microsomal triglyceride transfer protein (MTP), apolipoprotein B (apoB), and apolipoprotein CIII (apoCIII), or the expression of genes associated with glucose metabolism, such as phosphenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase).
  • MTP microsomal triglyceride transfer protein
  • apoB apolipoprotein B
  • apoCIII apolipoprotein CIII
  • HNF4- ⁇ is expressed in the kidneys and intestines as well as in the liver, and is widely associated with energy metabolism in vivo or maintenance of homeostasis, such as synthesis, transport, and secretion of fatty acids and regulation of cell cycle.
  • PPCK phosphenolpyruvate carboxykinase
  • G6Pase glucose-6-phosphatase
  • HNF4- ⁇ is known to control not only the transcription of genes necessary in the processes of metabolism of cholesterol, fatty acids, and glucose and decomposition in the liver, but also the transcription of representative drug-metabolizing enzymes, such as cytochrome P450 2D6 (CYP2D6), cytochrome P450 2B6 (CYP2B6), cytochrome P450 3A4 (CYP3A4), and cytochrome P450 2C9 (CYP2C9).
  • CYP2D6 cytochrome P450 2D6
  • CYP2B6 cytochrome P450 2B6
  • CYP3A4 cytochrome P450 3A4
  • CYP2C9 cytochrome P450 2C9
  • HNF4- ⁇ may render the capabilities of controlling lipid metabolism and glucose metabolism, and may be effectively used to develop an agent for preventing or improving hypertriglyceridemia, fatty liver, and diabetes.
  • SHP small heterodimer partner
  • FXR farnesoid X receptor
  • long-chain fatty acid acyl CoA palmitoyl CoA, myristoyl-CoA, dodecanoyl-CoA, stearoyl-CoA, linoleoyl-CoA, liolenoyl CoA, eicosapentaenoyl-CoA, docosahexaenoyl-CoA
  • SHP small heterodimer partner
  • FXR farnesoid X receptor
  • Japanese Patent Application Publication No. 2008-133247 discloses nitrogenistein, which is an inhibitor of HNF4- ⁇ activity for preventing or improving fatty liver or diabetes
  • International Patent Publication No. WO2002-024227 discloses that HNF4 ⁇ protein is overexpressed in colorectal tissues and that inhibiting HNF4 ⁇ protein can inhibit the proliferation of tumor cells
  • U.S. Patent Application Publication No. 2010-0286220 discloses the BIM5078 compound as a HNF4- ⁇ antagonist.
  • gastric cancer being a malignant tumor occurring in the stomach, includes gastric adenocarcinoma developing on the epithelium of the stomach, a malignant lymphoma developing on the submucosa, myosarcoma, interstitial tumor, etc., but generally refers to gastric adenocarcinoma.
  • gastric cancer can be classified into early gastric cancer, locally advanced gastric cancer, locally advanced invasive gastric cancer, or metastatic gastric cancer, etc.
  • the present inventors have confirmed through previous studies that HNF4- ⁇ is overexpressed in an early stage of gastric cancer to thereby increase the expression of Wnt5a, and have also confirmed that when shRNA is used to inhibit the expression of the HNF4- ⁇ gene, or the HNF4- ⁇ antagonist is treated, the formation of tumors can be inhibited by controlling the Wnt signal.
  • HNF4- ⁇ antagonists for preventing and treating gastric cancer
  • the present inventors have selected the compounds which can inhibit the activity of HNF4- ⁇ by specifically binding to the HNF4- ⁇ of the ligand binding domain, and have confirmed that the selected compounds can specifically reduce the expression of Wnt5a and significantly inhibit the growth of gastric cancer, thereby completing the invention.
  • an object of the present invention is to provide an HNF4- ⁇ antagonist which specifically binds to the ligand binding domain of HNF4- ⁇ and inhibits the activity of HNF4- ⁇ , and a pharmaceutical composition which is for preventing and treating gastric cancer and includes the HNF4- ⁇ antagonist as an active ingredient.
  • Formula 1 may be expressed by the following Formula 3,
  • the present invention also provides a hepatocyte nuclear factor 4 alpha (HNF4- ⁇ ) antagonist including at least one type selected from the group consisting of at least one type of a compound selected from the group consisting of the following Formula 6 and Formulas 6-1 to 6-10, which are derivatives of Formula 6; and salts thereof.
  • HNF4- ⁇ hepatocyte nuclear factor 4 alpha
  • the present invention also provides a hepatocyte nuclear factor 4 alpha (HNF4- ⁇ ) antagonist including at least one type selected from the group consisting of at least one type of a compound selected from the group consisting of the following Formula 7 and Formulas 7-1 to 7-5, which are derivatives of Formula 7; and salts thereof.
  • HNF4- ⁇ hepatocyte nuclear factor 4 alpha
  • the present invention also provides a hepatocyte nuclear factor 4 alpha (HNF4- ⁇ ) antagonist including at least one type selected from the group consisting of at least one type of a compound selected from the group consisting of the following Formula 8 and Formula 8-1, which is a derivative of Formula 8; and salts thereof.
  • HNF4- ⁇ hepatocyte nuclear factor 4 alpha
  • the HNF4- ⁇ antagonist may reduce the expression of wingless-type MMTV integration site family, member 5A (Wnt5a) by inhibiting the activity of HNF4- ⁇ .
  • FIG. 4 is data illustrating the changes in energy when the compounds expressed by Formula 3 and Formula 4, which are HNF4- ⁇ antagonists, and the BIM5078, which was used as a positive control, are bound to the ligand binding domain of HNF4- ⁇ ;
  • HNF4- ⁇ antagonists capable of inhibiting the activity of HNF4- ⁇ have been studied for the treatment of various diseases occurring due to the overexpression of HNF4- ⁇ , and the present inventors have discovered that inhibiting the activity of the overexpressed HNF4- ⁇ can inhibit tumorigenesis by controlling the Wnt signal, and have attempted to select HNF4- ⁇ antagonists for preventing and treating gastric cancer.
  • R 1 to R 5 are each independently a hydrogen atom (H), an oxygen atom (O), a nitro group (NO 2 ), a halogen atom, a C 1-6 alkyl group substituted with one to six identical or different halogen atoms, or a C 1-6 alkyl group.
  • the halogen atom may be, for example, at least one type of an atom selected from the group consisting of bromine (Br), chlorine (Cl), fluorine (F), and iodine (I); and the C 1-6 alkyl group, being a linear or branched saturated hydrocarbon having 1 to 6 carbon atoms, may be at least one type selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl groups.
  • NO 2 may be positioned in R 2 or R 4 , or a halogen atom may be positioned in R 3 , or more preferably, Formula 1 may be expressed by the following Formula 3.
  • NO 2 may be positioned in R 3 , or a C 1-6 alkyl group which can be substituted with one to six identical or different halogen atoms may be positioned in R 2 or R 4 , or more preferably, Formula 4, may be expressed by the following Formula 4.
  • the HNF4- ⁇ antagonist expressed by Formula 1 and Formula 2, or the HNF4- ⁇ antagonist expressed by Formula 3 and Formula 4 may specifically bind to the ligand binding domain of HNF4- ⁇ , and the activity of HNF4- ⁇ can be inhibited by the binding.
  • FIG. 1A is a schematic diagram illustrating the structure of HNF4- ⁇ protein.
  • the HNF4- ⁇ protein consists of a DNA binding domain, the ligand binding domain, and a transactivation domain, and the HNF4- ⁇ antagonist specifically binds to the ligand binding domain of HNF4- ⁇ and thereby inhibits the activity of HNF4- ⁇ .
  • FIG. 1B is a schematic diagram illustrating the diseases that may occur due to the overexpression of HNF4- ⁇ protein.
  • HNF4- ⁇ is known to cause diseases such as diabetes, atherosclerosis, hemophilia, thrombosis, hypoxia, medium chain acyl-CoA dehydrogenase (MCAD) deficiency, ornithine transcarbamylase (OTC) deficiency, cancer caused by hepatitis B virus (HBV), etc.
  • MCAD medium chain acyl-CoA dehydrogenase
  • OTC ornithine transcarbamylase
  • FIG. 2 is a schematic diagram illustrating the basic structures of naphthofuran and myristic acid, and a schematic diagram illustrating the feature that naphthofuran and myristic acid bind to the ligand binding domain of HNF4- ⁇ , and the docking energy of naphthofuran and myristic acid to the ligand binding domain of HNF4- ⁇ are ⁇ 6.8 and ⁇ 5.9, respectively. In the docking energy, as the “ ⁇ ” value becomes larger the binding becomes stronger.
  • the present invention also provides a hepatocyte nuclear factor 4 alpha (HNF4- ⁇ ) antagonist including at least one type selected from the group consisting of at least one type of a compound selected from the group consisting of the following Formula 7 and Formulas 7-1 to 7-5, which are derivatives of Formula 7; and salts thereof
  • HNF4- ⁇ hepatocyte nuclear factor 4 alpha
  • the present invention also provides a hepatocyte nuclear factor 4 alpha (HNF4- ⁇ ) antagonist including at least one type selected from the group consisting of at least one type of a compound selected from the group consisting of the following Formula 8 and Formula 8-1, which is a derivative of Formula 8; and salts thereof.
  • HNF4- ⁇ hepatocyte nuclear factor 4 alpha
  • the present invention also provides a pharmaceutical composition which is for preventing and treating cancer and includes the HNF4- ⁇ antagonist as an active ingredient, and a health functional food which is for preventing and improving cancer and includes the HNF4- ⁇ antagonist as an active ingredient.
  • the HNF4- ⁇ antagonist can reduce the expression of wingless-type MMTV integration site family, member 5A (Wnt5a) by inhibiting the activity of HNF4- ⁇ .
  • HNF4- ⁇ promotes the expression of the Wnt5a gene by binding to the promoter region of the Wnt5a gene. Therefore, the HNF4- ⁇ antagonist can inhibit the binding of HNF4- ⁇ to the promoter region of the Wnt5a gene by specifically binding to the ligand binding domain of HNF4- ⁇ , and as a result, reduce the Wnt5a expression, and is thereby capable of controlling the Wnt signal.
  • various gastric cancer cell lines were treated with the HNF4- ⁇ antagonist in order to confirm whether the HNF4- ⁇ antagonist selected in the present invention can be used as a therapeutic agent for preventing or treating gastric cancer.
  • the HNF4- ⁇ antagonist treatment resulted in the inhibition or apoptosis of the gastric cancer cell lines, and also in a significant reduction of Wnt5a expression in each of the gastric cancer cells treated with the HNF4- ⁇ antagonist.
  • the transplanted mouse showed a significant reduction in the size of tumor cells compared to the negative control group not treated with the HNF4- ⁇ antagonist.
  • the HNF4- ⁇ antagonist selected in the present invention specifically binds to the ligand binding domain of HNF4- ⁇ , and that the HNF4- ⁇ antagonist of the present invention can specifically reduce the expression of Wnt5a and inhibit the growth of gastric cancer cells compared to the existing HNF4- ⁇ antagonists, thus being applicable to a pharmaceutical composition or a health functional food for preventing and treating gastric cancer.
  • HNF4- ⁇ antagonist selected in the present invention may be applicable to a composition for treating or preventing diseases that may occur due to the overexpression of HNF4- ⁇ .
  • the HNF4- ⁇ antagonist selected in the present invention may be used for the preparation of a therapeutic agent for treating cancer.
  • the HNF4- ⁇ antagonist selected in the present invention is characterized in that it enables the expression of wingless-type MMTV integration site family, member 5A (Wnt5a) by inhibiting the activity of HNF4- ⁇ .
  • the present invention provides a method for treating cancer characterized in that the method includes administering to a subject in need thereof an effective amount of the HNF4- ⁇ antagonist selected in the present invention.
  • the HNF4- ⁇ antagonist of the present invention may be a compound expressed by Formula 1 or Formula 2, and most preferably a compound expressed by Formula 3.
  • the HNF4- ⁇ antagonist and a pharmaceutically acceptable salt thereof may be administered via various routes including oral, transdermal, subcutaneous, intravenous, and intramuscular administrations.
  • an effective amount refers to an amount which exhibits the effects of treating and preventing cancer, and inhibiting cancer metastasis when administered to a subject
  • the term “subject” used herein may refer to an animal, preferably, a mammal including humans, and may be cells, tissues, organs, etc., derived from the animal. The subject may be a patient in need of treatment.
  • an appropriate daily dose as a single dose or a divided dose required for treatment is an amount of about 0.01 mg to 750 mg/kg, preferably 0.1 mg to 100 mg, and most preferably 0.5 mg to 25 mg, however, the specific dose for each individual patient may vary depending on the particular compound, weight, sex, diet of a patient, administration time of drugs, administration method, excretion rate, combination of drugs, health conditions of a patient, age, etc.
  • the pharmaceutical composition for preventing or treating cancer including the HNF4- ⁇ antagonist according to the present invention, or the health functional food for preventing or improving cancer may further include other natural materials or compounds with an anticancer effect.
  • the pharmaceutical composition of the present invention may be administered to mammals including rats, mice, cattle, humans, etc., via various routes including oral, transdermal, subcutaneous, intravenous, and intramuscular administrations. Additionally, the pharmaceutical composition for preventing or treating cancer including the HNF4- ⁇ antagonist according to the present invention may be prepared in various formulations.
  • the formulation may be formulated using a conventional diluent or excipient such as a filler, an extender, a binder, a humectant, a disintegrant, a surfactant, etc.
  • Solid formulations for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid formulations may be prepared by adding at least one excipient, such as starch, sucrose, lactose, gelatin, etc., to the HNF4- ⁇ antagonist. Additionally, lubricants may be used in addition to the simple excipient.
  • Liquid formulations for oral administration may include suspensions, liquid medicine for internal use, emulsions, syrups, etc., and various excipients such as humectants, sweeteners, fragrances, and preservatives, may be used, in addition to the simple diluents such as water and liquid paraffin.
  • the kind of the health functional food which is for preventing and improving cancer and includes the HNF4- ⁇ antagonist as an active ingredient may not be particularly limited, and may be, for example, meats, sausages, bread, chocolates, candies, snacks, cookies, pizzas, ramen, other noodles, gums, dairy products including ice cream, various kinds of soups, beverages, teas, drinks, alcoholic beverages, vitamin complexes, etc.
  • a health supplement which is for preventing and improving cancer and includes the HNF4- ⁇ antagonist as an active ingredient may be prepared by adding and mixing nutrient supplementary components (vitamins B1, B2, B5, B6, and E and acetic acid ester, and nicotinic acid amide), oligosaccharides, 50% ethanol, and distilled water to the HNF4- ⁇ antagonist to form a granular phase, drying in a dryer under vacuum, passing through a 12 to 14 mesh to prepare uniform granules, and subjecting an adequate amount of the obtained granules to extrusion molding to prepare tablets or powders, or filling them into soft capsules to prepare soft capsule products.
  • nutrient supplementary components vitamins B1, B2, B5, B6, and E and acetic acid ester, and nicotinic acid amide
  • oligosaccharides 50% ethanol
  • 50% ethanol 50% ethanol
  • distilled water distilled water
  • the effective dose of the HNF4- ⁇ antagonist contained in the health food may based on the effective dose of the pharmaceutical composition, and the combined amount of active ingredients may be appropriately determined according to the purpose of use, such as preventive or therapeutic treatment. In the case of a long-term intake for the purpose of health and sanitation or health control, the dose may be less than the above range.
  • the selected candidate materials 1 to 20 had naphthofuran as a basic structure, and the selected candidate materials 21 to 40 had myristic acid as a basic structure.
  • HNF4- ⁇ antagonist candidate materials 1 to 10 Structure (CID)
  • CID Structure
  • Lowest E Naphthofuran ⁇ 6.8 1 23055118 ⁇ 11.00 2 23345854 ⁇ 11.00 3 3649084 ⁇ 10.40 4 2943931 ⁇ 10.30 5 3904673 ⁇ 10.30 6 2404390 ⁇ 10.00 7 35728809 ⁇ 10.00 8 66661464 ⁇ 10.00 9 7935304 ⁇ 10.00 10 3282588 ⁇ 9.90
  • HNF4- ⁇ antagonist candidate materials 11 to 20 Structure (CID)
  • CID Structure
  • Lowest E 11 2089313 ⁇ 9.80 12 2397577 ⁇ 9.80 13 29617456 ⁇ 9.80 14 26796617 ⁇ 9.70 15 7900920 ⁇ 9.70 16 9839993 ⁇ 9.70 17 1323001 ⁇ 9.60
  • 2087412 ⁇ 9.60 19 2438477 ⁇ 9.60
  • HNF4- ⁇ antagonist candidate materials 31 to 40 Structure (CID) Lowest E 31 19593543 ⁇ 8.90 32 21773206 ⁇ 8.90 33 69919679 ⁇ 8.90 34 22383158 ⁇ 8.80 35 22157196 ⁇ 8.70 36 53783087 ⁇ 8.70 37 17764038 ⁇ 8.60 38 20320744 ⁇ 8.60 39 44625744 ⁇ 8.60 40 59582177 ⁇ 8.60
  • the docking energy of the compounds selected in the first selection was in the range of ⁇ 11.0 kcal/mol to ⁇ 9.6 kcal/mol, and it was confirmed that the compounds more stably bind to the ligand binding domain of HNF4- ⁇ compared to those of naphthofuran and myristic acid with basic structures, the HNF4- ⁇ antagonists expressed by the following Formula 1 were drawn based on the candidate materials 3, 4, 5, 6, 7, 10, 12, and 14, and the HNF4- ⁇ antagonists expressed by the following Formula 2 were drawn based on the candidate materials 11, 17, and 18.
  • R 1 to R 5 are respectively H, NO 2 , a halogen atom, or a C 1-4 alkyl group substituted with a halogen atom.
  • the HNF4- ⁇ antagonists which can specifically bind to the ligand binding domain of HNF4- ⁇ were additionally selected, and the compounds expressed by the following Formulas 5 to 8 were prepared therefrom. Furthermore, the compounds expressed by Formulas 5-1 to 5-7, which are derivatives of Formula 5; the compounds expressed by Formulas 6-1 to 6-10, which are derivatives of Formula 6; the compounds expressed by Formulas 7-1 to 7-5, which are derivatives of Formula 7; and the compound expressed by Formula 8-1, which is a derivative of Formula 8, were additionally prepared, and the docking energy for each of the compounds with HNF4- ⁇ was measured.
  • Each of the gastric cancer cell lines was treated with the compound expressed by Formula 3 at concentrations of 0 ⁇ M, 20 ⁇ M, 40 ⁇ M, and 50 ⁇ M, respectively, for 48 hours. Then, the resultant was cultured in MTS assay solution for 2 hours and the survival rate of the cells was measured. MTS assay solution was used for analyzing the survival rate of the cells, and CellTiter 96® aqueous solution (Promega) was used. The experiment was performed three times in a 96-well plate.
  • the cell growth rate obtained in each experiment was calculated from the average value of the three experiments with the cell survival rate of the untreated negative control group set at 100%. The results are shown in FIG. 13 . According to the results, the compound expressed by Formula 3 apoptosized gastric cancer cells in a dose-dependent manner. It was confirmed that the gastric cancer cell lines were apoptosized to a level of about half at 50 ⁇ M of the compound.
  • the HNF4- ⁇ antagonists selected in the present invention were confirmed to specifically bind to the ligand binding domain of HNF4- ⁇ , thereby inhibiting the activity of HNF4- ⁇ .
  • the HNF4- ⁇ antagonists of the present invention can significantly reduce the expression of Wnt5a in a specific manner compared to that of the conventional known HNF4- ⁇ antagonists and inhibit the growth of gastric cancer cells. Therefore, the HNF4- ⁇ antagonists of the present invention can be used as a pharmaceutical composition or a health functional food for preventing and treating cancer.

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