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WO2020054981A1 - Composition pour le traitement ou la prévention du cancer comprenant le 2-(3-[2-(1-cyclohexen-1-yl)éthyl]-6,7-diméthoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl)-n-(4-éthylphényl)butanamide utilisé comme principe actif - Google Patents

Composition pour le traitement ou la prévention du cancer comprenant le 2-(3-[2-(1-cyclohexen-1-yl)éthyl]-6,7-diméthoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl)-n-(4-éthylphényl)butanamide utilisé comme principe actif Download PDF

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WO2020054981A1
WO2020054981A1 PCT/KR2019/010096 KR2019010096W WO2020054981A1 WO 2020054981 A1 WO2020054981 A1 WO 2020054981A1 KR 2019010096 W KR2019010096 W KR 2019010096W WO 2020054981 A1 WO2020054981 A1 WO 2020054981A1
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cancer
skin
formula
cells
composition
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Korean (ko)
Inventor
홍진태
이희범
김기천
김태훈
박전의
김지혜
권혜정
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Autotelic Bio Inc
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Autotelic Bio Inc
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Priority claimed from KR1020190097251A external-priority patent/KR102236686B1/ko
Publication of WO2020054981A1 publication Critical patent/WO2020054981A1/fr
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    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention is 2- (3- [2- (1-cyclohexen-1-yl) ethyl] -6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl)- It relates to a composition for the treatment or prevention of cancer comprising N- (4-ethylphenyl) butanamide (K284-6111) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Cancer also called malignant neoplasm, is a disease in which a group of cells causes uncontrolled growth, penetration, and sometimes metastasis, causing major health problems worldwide. Cancer is a disease caused by uncontrollable cell proliferation due to a defect in cell cycle regulation.
  • cancers are one of the incurable diseases that humans must solve, and despite the tremendous amount of capital invested in the development of healing to treat them worldwide, and the development of medical technology, the incidence of cancer and death from cancer continues to increase. Is in trend. According to the latest statistics from the World Health Organization, it is known that more than 10 million new cancer patients occur annually worldwide. In Korea, cancer is the highest cause of death, and more than 100,000 people are diagnosed annually, and more than 60,000 people are diagnosed with cancer. Is dying.
  • the object of the present invention is 2- (3- [2- (1-cyclohexen-1-yl) ethyl] -6,7-dimethoxy-4-oxo-3,4-dihydro-2-quina Zolinyl sulfanyl) -N- (4-ethylphenyl) butanamide or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer, and a pharmaceutical composition for preventing or improving cancer Is to provide
  • Another object of the present invention is 2- (3- [2- (1-cyclohexen-1-yl) ethyl] -6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazoli It is to provide a pharmaceutical composition for inhibiting metastasis of cancer and a health functional food composition comprising nilsulfanyl) -N- (4-ethylphenyl) butanamide or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of cancer comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for inhibiting metastasis of cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a health functional food composition for inhibiting metastasis of cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention is 2- (3- [2- (1-cyclohexen-1-yl) ethyl] -6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl)- N- (4-ethylphenyl) butanamide (K284-6111) or a composition for the treatment or prevention of cancer comprising a pharmaceutically acceptable salt thereof as an active ingredient, wherein the compound prevents and treats cancer, Furthermore, it is characterized by having an effect of suppressing metastasis of cancer cells.
  • 17 shows the results of performing a transmembrane analysis to confirm the effect of K284-6111 on A549 cells and H460 cell metastasis.
  • 19 to 21 are the results of measuring the number of tumors present in the metastasized lung tissue and the distribution of tumors per surface area, Hematoxylin & eosin (H & E) staining and immunohistochemical results when treated with K284-6111 in lung cancer metastasis mouse model. Respectively.
  • the present invention provides 2- (3- [2- (1-cyclohexen-1-yl) ethyl] -6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl) -N- (4-ethylphenyl) butanamide or a pharmaceutically acceptable salt thereof as an active ingredient, to provide a pharmaceutical composition for preventing or treating cancer, wherein 2- (3- [2- (1- Cyclohexen-1-yl) ethyl] -6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl) -N- (4-ethylphenyl) butanamide is represented by the following Chemical Formula 1 It is a compound represented by.
  • the compound of the present invention is characterized by having a prophylactic or therapeutic effect against cancer.
  • cancer refers to an aggressive characteristic in which cells divide and grow, ignoring normal growth limits, an invasive characteristic that penetrates surrounding tissue, and metastatic that spreads to other parts of the body. It is a generic term for diseases caused by cells with characteristics.
  • the cancer to be treated is not limited to types such as adenocarcinoma, solid cancer, blood cancer, and more specifically, breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer , Skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer , Prostate cancer, bronchial cancer, or bone marrow cancer, more preferably melanoma or lung cancer.
  • types such as adenocarcinoma, solid cancer, blood cancer, and more specifically, breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer , Skin or eye melanoma, uterine sarcoma, ovarian cancer,
  • the pharmaceutical composition for preventing or treating cancer of the present invention is 2- (3- [2- (1-cyclohexen-1-yl) ethyl] -6,7-dime, a compound represented by Formula 1 described above.
  • Form of a pharmaceutical composition comprising a pharmaceutically effective amount of methoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl) -N- (4-ethylphenyl) butanamide and a pharmaceutically acceptable carrier It can be provided as.
  • the pharmaceutically acceptable carrier included in the pharmaceutical composition of the present invention is commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, etc. It does not work.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
  • Suitable dosages of the pharmaceutical compositions of the present invention can be administered in a variety of ways depending on factors such as formulation method, mode of administration, patient's age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response sensitivity.
  • the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like.
  • the concentration of the active ingredient contained in the composition of the present invention is determined in consideration of the treatment purpose, the patient's condition, the required period, the severity of the disease, etc., and is not limited to a specific range of concentration.
  • the pharmaceutical composition of the present invention is prepared in a unit dose form by formulating using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily carried out by those skilled in the art to which the present invention pertains. Or it can be manufactured by incorporating into a multi-dose container.
  • the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of ex, powder, granule, tablet, or capsule, and may further include a dispersant or stabilizer.
  • the present invention provides a health functional food composition for preventing or improving cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cancer to be treated is not limited to types such as adenocarcinoma, solid cancer, blood cancer, and more specifically, breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer , Skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer , Prostate cancer, bronchial cancer, or bone marrow cancer, more preferably melanoma or lung cancer.
  • types such as adenocarcinoma, solid cancer, blood cancer, and more specifically, breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer , Skin or eye melanoma, uterine sarcoma, ovarian cancer,
  • the health functional food composition of the present invention may be provided in the form of a powder, granule, tablet, capsule, syrup or beverage, and the health functional food composition is used together with other foods or food additives other than the compound according to the present invention as an active ingredient , It can be suitably used according to a conventional method.
  • the mixing amount of the active ingredient may be appropriately determined according to its purpose of use, for example, prophylactic, health or therapeutic treatment.
  • the effective dose of the compound contained in the dietary supplement composition may be used according to the effective dose of the pharmaceutical composition, but may be below the above range for long-term intake for health and hygiene purposes or for health control purposes. There is no problem in terms of safety of the active ingredient, it is clear that it can be used in an amount above the range.
  • the present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for inhibiting metastasis of cancer, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • cancer metastasis refers to a condition in which a malignant tumor has spread from an affected organ to another tissue, and is formed by cancer cells spreading through blood circulation or lymph circulation. It has grown into a new tumor after the liver, or, alternatively, cancer cells can be formed by moving directly to neighboring tissues.
  • cancer metastasis is the spread of cancer cells by invasion, where cancer cells directly migrate and penetrate into neighboring tissues, and metastases that form new tumors in organs that are not physically adjacent to the primary cancer as cancer cells travel through the bloodstream (metastasis).
  • the metastasis inhibiting cancer is not limited to types such as adenocarcinoma, solid cancer, blood cancer, and more specifically, breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, two Cervical cancer, skin or ocular melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethra It may be cancer, prostate cancer, bronchial cancer, or bone marrow cancer, more preferably melanoma or lung cancer.
  • types such as adenocarcinoma, solid cancer, blood cancer, and more specifically, breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, two Cervical cancer, skin or ocular melanoma, uterine s
  • Hematoxylin and eosin solutions were purchased from Sigma-Aldrich (St. Louis, MO, USA).
  • mice were mice, randomly grown bodies weighing 24 to 28 g, and weighing 6 to 7 weeks of age. Animals were kept under controlled conditions of temperature and light (Light: dark, 10 h: 14 h). Mice were given a standard diet (procured by Malawistan Levers Ltd.) and water freely. B16F10 mouse melanoma was injected subcutaneously into 8 week old C57BL / 6 mice (2 ⁇ 10 5 tumor cells / 200 ⁇ l in phosphate buffered saline (PBS) with a 27 gauge needle). The next day, K284-6111 was injected intravenously at a concentration of 0.5 mg / kg, and once every 3 days during the 35 days of the experiment. After 15 days after melanoma injection, the tumor volume of the animals was monitored every 5 days. Tumor volume was measured with a Vernier caliper and calculated by the following equation.
  • mice were sacrificed with inhalants using carbon dioxide.
  • the tumor was isolated from the surrounding muscles and dermis and excised.
  • Melanoma tissue was dissected and immediately fixed in a 4% formaldehyde solution, dehydrated in ethanol (70-100%) by concentration, and embedded in paraffin. Tissues were sectioned with a rotary microtome (Sakura Finetek Europe BV, Alphen aan den Rijn, Netherlands) (4 ⁇ m thick) and stained with hematoxylin and eosin. The cross section was observed with an optical microscope (Olympus, Tokyo, Japan) and photographed at ⁇ 200 magnification. For IHC, melanoma tissue sections were blocked for 30 minutes with 3% normal horse serum diluted with PBS.
  • Sections were blotted and cultured at appropriate dilution multiples (1: 100 dilution) with Cyclin D1, MMP9, PCNA, Caspase-3, Chi3L1 and IL-13R ⁇ 2 antibodies blocking serum overnight at 4 ° C.
  • the avidin-biotin-peroxidase complex (ABC; Vector Laboratories, Burlingame, CA, USA) was washed.
  • the slides were washed, and the peroxidase reaction was developed with diaminobenzidine and peroxide, mounted on an Aqua-Mount and evaluated at ⁇ 200 magnification under an optical microscope (Olympus). A negative control was performed by omitting the primary antibody.
  • B16F10, A549 and H460 non-small cell lung cancer (NSCLC) cells and Lewis lung carcinoma (LLC) were obtained from the American Type Culture Collection (Manassas, VA).
  • A549 and H460 cells were cultured in RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum (FBS), 100U / mL penicillin and 100 ⁇ g / mL streptomycin.
  • FBS heat inactivated fetal bovine serum
  • B16F10 skin melanoma was cultured in DMEM supplemented with 10% heat-inactivated FBS, 100U / mL penicillin and 100 ⁇ g / mL streptomycin.
  • Cell culture was carried out in an incubator at 37 ° C. in a humidified atmosphere of 5% CO 2 .
  • A549, H460 cell lines were dispensed into 96-well plates. The next day, cells were treated with K284-6111 (0-5 ⁇ M) for 24 hours, followed by MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] analysis (Sigma Aldrich, St. Louis, MO) was analyzed according to the manufacturer's instructions. Briefly MTT (5 mg / mL) was added and the plate was incubated at 37 ° C. for 4 hours before dimethyl sulfoxide (100 ⁇ L) was added to each well. Finally, the absorbance of each well was read at a wavelength of 540 nm using a plate reader.
  • Melanoma tumor tissue was homogenized using the EzRIPA lysis kit (ATTO, Tokyo, JP).
  • A549 and H460 cells were homogenized with a protein extraction solution (PRO-PREPTM; Intron Biotechnology) after the experiment and lysed by incubation on ice for 60 minutes. Tissue and cell lysates were centrifuged at 13,000 x g for 15 min at 4 ° C. The same amount of protein (20 ⁇ g) was separated by 12% SDS-PAGE and then transferred to a polyvinylidene fluoride membrane (GE Water and Process technologies).
  • A549 cells were plated at a density of 1x10 5 cell / ML in 6-well cell culture plates for overnight compliance and treated for 48 hours or at various concentrations of K284-6111. After treatment, cells were harvested by trypsin treatment and fixed in ice cold 70% methanol at 4 ° C. overnight. Cells were then centrifuged at 300 xg for 5 minutes and incubated with propidium iodide (PI) working solution (100 ⁇ g / ml PI and 100 ⁇ g / ml RNaseA) for 30 minutes at 37 ° C. Cell cycle distribution was analyzed using a flow cytometer (FACSCalibur; BD Biosciences, Franklin Lakes, NJ, USA).
  • PI propidium iodide
  • A549 cells were plated in a 12-well plate (1 x 10 5 cell / well) and the Chi3L1-Luc plasmid (Stratagene, La Jolla, CA) using a mixture of plasmid and Lipofectamine 3000 in OPTI-MEM according to the manufacturer's instructions. ) Was transiently transfected (Invitrogen, Carlsbad, CA) for 24 hours. The transfected cells were further treated with 10 ⁇ g / mL for 24 hours. Luciferase activity was measured using a luciferase assay kit (Promega, Madison, USA) and a luminometer described in the manufacturer's specifications (WinGlow, Bad Wildbad, Germany).
  • A549 and H460 cells (7 ⁇ 10 5 cells) were transferred to a 60 mm dish and incubated in a 37 ° C. incubator (5% CO 2 ) until the cells returned to normal. Cells were treated with K284-6111 for 24 hours. Then, both adherent and floating cells were harvested using 0.25% trypsin-EDTA. The harvested cells were transferred to a tube and centrifuged. Pelleted cells were washed with cold PBS and propidium iodide (PI) (Sigma-Aldrich) (40 ⁇ g / mL), RNase (100 ⁇ g / mL) (Gibco) and TritonX-100 (Sigma-Aldrich) incubated at 37 ° C. for 10 min. Did. Samples were analyzed using fluorescence-activated cell sorting. The percentage of cells in G1, S and G2 / M phases was calculated using Cell Quest.
  • PI propidium iodide
  • the migration of human lung cancer cells A549 and H460 was performed quantitatively in a permeable insert (8 ⁇ m pore trans-well, Corning Inc.). 5 ⁇ M of K284-6111 treated A549 and H460 cells were plated at 2.0 ⁇ 10 4 cells per well and incubated in a humidified incubator at 37 ° C., 5% CO 2 for 17 hours. After incubation, cells were fixed with 3.7% formaldehyde for 2 minutes, and then washed twice with 1XPBS. Next, the cells were infiltrated with 100% methanol for 15 minutes and stained with trypan blue for 20 minutes. Non-mobile cells inside the wells were removed with a cotton swab, and images taken at 200 times magnification under an optical microscope (Olympus) were analyzed using NIH ImageJ software.
  • a permeable insert 8 ⁇ m pore trans-well, Corning Inc.
  • A549 and MDA-MB-231 cells are plated in 6-well plates using 6 ⁇ 10 5 cells / well culture medium (10% FBS RPMI 1640 with 1% AA) and attached in the incubator for one day. The bottom of the plate to which the cells are attached is scratched at equal intervals, and then washed twice with phosphate buffered saline (PBS) to remove suspended cells.
  • PBS phosphate buffered saline
  • A549 and H460 cells were cultured on 8-chamber slides and then treated with K284-6111 (0-5 ⁇ M) for 24 hours. Cells were washed twice with phosphate buffered saline (PBS) and fixed by incubation in 4% paraformaldehyde in PBS for 1 hour at room temperature. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis was performed according to the manufacturer's instructions using the DeadEnd TM Fluorometric TUNEL system (Promega, Madison, WI). The total cell number in a given area was determined using DAPI staining. The apoptosis index was determined by dividing the number of TUNEL positive stained cells by the total number of cells x 100%.
  • TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labeling
  • a lung cancer metastasis mouse model was produced.
  • Body weight loads of 6-7 weeks of age were performed on random growers, male C57BL / 6 mice. Animals were kept under controlled conditions of temperature and light (Light: dark, 10 h: 14 h). Mice were given a standard diet (procured by Malawistan Levers Ltd.) and water freely.
  • B16F10 mouse melanoma was injected intravenously into the tail of an 8 week old C57BL / 6 mouse (4 ⁇ 10 4 tumor cells / 100 ⁇ l in phosphate buffered saline (PBS) with a 27 gauge needle).
  • PBS phosphate buffered saline
  • K284-6111 was injected intravenously at a concentration of 0.5 mg / kg, and injected twice a week (Tuesday and Gold) for 4 weeks. After the experiment, animals were sacrificed by inhaling carbon dioxide. The lung tissue was separated from the diaphragm and the heart so that the tissue was not damaged.
  • FIG. 1 is a picture obtained from B16F10 melanoma injected subcutaneously into C57BL / 6 mice, and after melanoma injection, K284-6111 was injected intravenously through the tail 10 times at intervals of 3 days at a dose of 0.5 mg / kg. As a result, the size of melanoma was significantly reduced as shown in the photo below.
  • FIG. 3 is a section stained with H & E of dissected melanoma tumors of the control group, and hematoxylin and eosin (H & E) staining sites of melanoma tumor sections show melanoma-induced, intact tumor cell structure.
  • Tumors treated with K284-6111 showed cracking in the non-cracked area between the cells and the death of cells around the blood vessels.
  • IHC against PCNA CyclinD1, MMP9, PCNA, cleaved caspase-3, Chi3L1 and IL-13R ⁇ 2 in mouse B16F10 melanoma tissue, different protein expression was observed.
  • Figure 5 shows the results of Western blot analysis of the cell proliferation gene contained in the lysate of melanoma tissue of C57BL / 6 mice injected with melanoma subcutaneously.
  • the relative protein expression of the K284-6111 treatment group compared to the control group is shown in the lower graph.
  • K284-6111 treatment it was confirmed that the expression level of genes involved in cell proliferation was significantly reduced.
  • FIG. 6 is a result of Western blot analysis of apoptosis-related genes from the lysate of melanoma tissue of C57BL / 6 mice injected with melanoma subcutaneously.
  • the relative protein expression of the K284-6111 treatment group compared to the control group is shown in the lower graph.
  • the expression level was increased in Cleaved-Caspase-3, Bax, p21, and p53 when K284-6111 was treated.
  • FIG. 7 shows Western blot analysis for phosphorylation of MAPK, Akt and AP1 (c-Jun and c-Fos) from the lysate of melanoma tissues of C57BL / 6 mice injected with melanoma subcutaneously, and compared with the control group K284
  • the relative protein expression of the -6111 treatment group is shown in the lower graph. In the case of p-p38, the expression level was increased, but other factors confirmed that the expression level was decreased.
  • FIG. 8 is a result of measuring the viability of each cell
  • FIG. 8A shows the results for A549 cells
  • FIG. 8B shows the results for H460 cells.
  • A549 cells and H460 cells were treated with 0-5 ⁇ M of K284-6111 for 48 hours, and cell viability was measured by MTT analysis. Data are expressed as mean ⁇ SD of 3 experiments. (* P ⁇ 0.05 vs. control. #P ⁇ 0.01 vs. control.) As a result, it was confirmed that the cell viability decreased as the concentration of K284-6111 increased in both cell lines. It was confirmed that A549 cells had an IC 50 of 2.7 ⁇ M and H460 of 2.5 ⁇ M.
  • FIG. 9 is a result of Western blot analysis of the cell cycle regulatory genes of the A549 cell line and the H460 cell line treated with K284-6111.
  • Figure 9A shows the results for A549 cells
  • Figure 9B shows the results for H460 cells. From each result, it was confirmed that as the treatment concentration of K284-6111 increased, the expression level of the related gene decreased.
  • FIG. 10 is a result of Western blot analysis for apoptosis-related genes in the A549 cell line and the H460 cell line treated with K284-6111, FIG. 10A shows the result for A549 cells, and FIG. 10B shows the result for H460 cells.
  • K284-6111 was dose-dependent.
  • FIG. 11 is a result of Western blot analysis for MAPK, Akt, and AP1 phosphorylated in K284-6111 treated A549 cell line and H460 cell line, FIG. 11A shows the result for A549 cell, and FIG. 11B shows the result for H460 cell.
  • K284-6111 was dose-dependent.
  • FIG. 13 shows the results of processing K284-6111 by concentration to measure the effect of K284-6111 on the cell cycle
  • FIG. 14 shows the transwell (trans-) of A549 and H460 cell lines treated with 5 ⁇ M of K284-6111 well migration).
  • TUNEL analysis was performed to confirm the effect on cell death in dose-dependent treatment of K284-6111 in A549 cell line and H460 cell line. 15 and 16 show the results for each cell line, and it can be confirmed that the effect on cell death is increased depending on the concentration.
  • 17 is a result of performing a transmembrane analysis to confirm the effect of K284-6111 on A549 cell and H460 cell metastasis, and it was observed that the drug inhibits cell migration in a concentration-dependent manner at 0-5 ⁇ M. .
  • the number of tumors and the distribution of tumors per surface area, hematoxylin & eosin (H & E) staining and immunohistochemical results were measured in lung tissue with cancer metastasized from C57BL / 6 mice.
  • FIG. 19 is a photograph obtained from lung tissue of a lung cancer metastasis model induced by tail vein injection into C57BL / 6 mice.
  • B16F10 melanoma was injected with physiological saline through the tail of C57BL / 6 mice, and intravenous injection was performed 2 days later.
  • K284-6111 with a dose of 0.5 mg / kg twice a week for 8 times, and intravenously through the tail, lung cancer metastasis was significantly reduced as shown in the photo.
  • 21 is a section of lung tissue metastasized with H & E stained from lung cancer metastasis model, and it is possible to identify a tumor that is clustered in a form other than the lung tissue inside the lung tissue.
  • the metastasized tumors of mice injected with K284-6111 show that the population is significantly reduced compared to the control group.

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Abstract

La présente invention concerne une composition pour le traitement ou la prévention du cancer comprenant, utilisé comme principe actif, le 2-(3-[2-(1-cyclohexen-1-yl)éthyl]-6,7-diméthoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl)-N-(4-éthylphényl)butanamide (K284-6111) ou un sel pharmaceutiquement acceptable de celui-ci, le composé ayant des effets de prévention et de traitement du cancer et également d'inhibition de la métastase de cellules cancéreuses.
PCT/KR2019/010096 2018-09-13 2019-08-09 Composition pour le traitement ou la prévention du cancer comprenant le 2-(3-[2-(1-cyclohexen-1-yl)éthyl]-6,7-diméthoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl)-n-(4-éthylphényl)butanamide utilisé comme principe actif Ceased WO2020054981A1 (fr)

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WO2005049613A1 (fr) * 2003-11-14 2005-06-02 Merck Sharp & Dohme Limited Pyrimidine-4-(3h)-ones bicycliques, leurs analogues et derives modulant la fonction du recepteur de vanilloide-1 (vr1)
EP2740727A1 (fr) * 2012-12-07 2014-06-11 King Saud University Analogues de quinazolinone destinés à être utilisés en tant qu'agents anticonvulsivants

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WO2005049613A1 (fr) * 2003-11-14 2005-06-02 Merck Sharp & Dohme Limited Pyrimidine-4-(3h)-ones bicycliques, leurs analogues et derives modulant la fonction du recepteur de vanilloide-1 (vr1)
EP2740727A1 (fr) * 2012-12-07 2014-06-11 King Saud University Analogues de quinazolinone destinés à être utilisés en tant qu'agents anticonvulsivants

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CHOI, J. Y. ET AL.: "K284-6111 prevents the amyloid beta-induced neuroinflammation and impainnent of recognition memory through inhibition of NF-kappaB-mediated CHI3L1 expression", JOURNAL OF NEUROINFLAMMATION, vol. 15, no. 224, 11 August 2018 (2018-08-11), pages 1 - 13, XP055693963 *
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