WO2022025709A1 - 2,3,5-치환된 싸이오펜 화합물의 위장관기질종양 예방, 개선 또는 치료 용도 - Google Patents
2,3,5-치환된 싸이오펜 화합물의 위장관기질종양 예방, 개선 또는 치료 용도 Download PDFInfo
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- WO2022025709A1 WO2022025709A1 PCT/KR2021/009987 KR2021009987W WO2022025709A1 WO 2022025709 A1 WO2022025709 A1 WO 2022025709A1 KR 2021009987 W KR2021009987 W KR 2021009987W WO 2022025709 A1 WO2022025709 A1 WO 2022025709A1
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- gastrointestinal stromal
- stromal tumor
- kit
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/30—Other Organic compounds
Definitions
- the present invention relates to the use of a 2,3,5-substituted thiophene compound for the prevention, improvement or treatment of gastrointestinal stromal tumors.
- Gastrointestinal stromal tumor is the most common sarcoma occurring in the gastrointestinal tract, mesentery, or reticulum, accounting for 5% of all sarcomas. In general, only complete resection can achieve a cure for gastrointestinal stromal tumor, but recurrence to the liver or peritoneum is common even after surgery. Its prognosis was very poor. A phenomenal effect could be achieved by using imatinib (imatinib, Glivec , Novartis), a so-called targeted anticancer drug that can block specific cell signaling systems related to the development of gastrointestinal stromal tumors.
- imatinib imatinib, Glivec , Novartis
- Gleevec exhibits very mild side effects compared to previous cytotoxic anticancer drugs, it showed excellent effects not only in prolonging the survival period but also in quality of life. As an adjuvant treatment after treatment and surgery, research on the effect of Gleevec is ongoing.
- Gastrointestinal stromal tumor originates from Cajal stromal cells or its progenitor cells, and is a mesenchymal tumor of the gastrointestinal tract induced by KIT mutations (D816, N822K). Most cases (90-95%) are positive for c-kit protein and have characteristic spindle, epithelial or mixed histological findings (Corless CL, Fletcher JA, Heinrich MC. Biology of gastro-intestinal stromal tumors. J Clin Oncol) 2004;22:3813-3825.). Mutations in the KIT or PDGFR ⁇ gene are found in 85-90% of gastrointestinal stromal tumors, of which the KIT gene mutation is the most common with a frequency of 75-80%.
- mutations in exon 11 account for about 70%, exon 9 mutations in about 15%, and mutations in exons 13 and 17 less than 5% are rare.
- Mutations in the PDGFR ⁇ gene are observed in about 1/3 (about 7%) of gastrointestinal stromal tumors without KIT mutations (Yarden Y, Kuang WJ, Yang-Feng T, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 1987;6:3341-3351.).
- KIT receptor protein is activated by itself even in the absence of ligand stimulation due to KIT gene mutations (D816, N822K), and cell division is continuously promoted to generate tumors.
- Gastrointestinal stromal tumors are known to have a similar incidence worldwide regardless of race. Gastrointestinal stromal tumor is a relatively rare tumor, with an annual incidence of 10-20 per million people, and it is known that about 20-30% of all gastrointestinal stromal tumors show a clinically malignant course (Miettinen M, Lasota J. Gastrointestinal stromal tumors: definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1-12.). Considering that the population of Korea is about 50 million, 500-1,000 new cases of gastrointestinal stromal tumor occur annually, and it is estimated that the number of patients with a malignant course will be about 100-300 annually. It occurs slightly more in men than in women, and it occurs most often in people aged 55-65, but it also occurs in people in their 20s and 30s and in children.
- the present inventors completed the present invention by conducting research to develop a novel material that can be used for the treatment of gastrointestinal stromal tumor.
- One object of the present invention is to provide a pharmaceutical composition for preventing or treating gastrointestinal stromal tumor, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- Another object of the present invention is to provide a food composition for preventing or improving gastrointestinal stromal tumor comprising a compound represented by the following formula (1) or an acceptable salt thereof:
- Another object of the present invention is to provide a method for treating gastrointestinal stromal tumor comprising administering to a patient with a gastrointestinal stromal tumor a pharmaceutical composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to do:
- Another object of the present invention is to provide the use of a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof for preventing or treating gastrointestinal stromal tumor:
- One aspect of the present invention provides a pharmaceutical composition for preventing or treating gastrointestinal stromal tumor comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- the gastrointestinal stromal tumor may be generated by substituting valine for aspartic acid, amino acid 816 constituting the c-kit protein.
- Another aspect of the present invention provides a food composition for preventing or improving gastrointestinal stromal tumor comprising a compound represented by the following formula (1) or an acceptable salt thereof:
- Another aspect of the present invention is a method of treating a gastrointestinal stromal tumor comprising administering to a patient with a gastrointestinal stromal tumor a pharmaceutical composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to provide:
- Another aspect of the present invention provides the use of a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof for preventing or treating gastrointestinal stromal tumor:
- Another aspect of the present invention provides the use of a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for preventing or treating gastrointestinal stromal tumor:
- composition containing the 2,3,5-substituted thiophene compound according to an embodiment of the present invention has an excellent rate of inhibition of gastrointestinal stromal tumor growth, it can be usefully utilized for the prevention, improvement or treatment of gastrointestinal stromal tumor.
- FIG. 1 is a diagram showing a mutation in which the 816th amino acid of the c-kit protein amino acid sequence is substituted with aspartic acid (D) to valine (V).
- FIG. 2 is a c-kit D816V Ba / F3 cell line according to the treatment concentration of (A) PHI-101, (B) sunitinib and (C) dasatinib according to an embodiment of the present invention; This is a picture showing my ability to inhibit signal transduction.
- FIG. 4 is a cell of c-kit D816V Ba/F3 cell line treated with (A) negative control, DMSO (dimethyl sulfoxid), (B) sunitinib, and (C) PHI-101 according to an embodiment of the present invention. It is a graph showing the results of cycle FACS analysis.
- FIG. 5 is each of the c-kit D816V Ba/F3 cell lines treated with (A) negative controls DMSO (dimethyl sulfoxid), (B) sunitinib, and (C) PHI-101 according to an embodiment of the present invention. It is a graph showing the population by cell cycle.
- A negative controls DMSO (dimethyl sulfoxid), (B) sunitinib, and (C) PHI-101 according to an embodiment of the present invention. It is a graph showing the population by cell cycle.
- FIG. 6 is a photograph showing the signaling inhibition ability in the GIST-T1 cell line according to the treatment concentration of PHI-101, imatinib (Imatinib) and sunitinib according to an embodiment of the present invention.
- FIG. 7 is a photograph showing the results of confirming the apoptosis effect of the GIST-T1 cell line according to the treatment concentrations of PHI-101, imatinib, and sunitinib according to an embodiment of the present invention by a Western blot analysis method.
- FIG. 8 is a graph and table showing the survival period extension effect of oral administration of PHI-101, imatinib and sunitinib according to an embodiment of the present invention in a c-kit D816V Ba/F3 cell line xenograft mouse model.
- One aspect of the present invention provides a pharmaceutical composition for preventing or treating gastrointestinal stromal tumor comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
- the compound represented by Formula 1, included as an active ingredient in the pharmaceutical composition of the present invention is (S)-5-((3-fluorophenyl)ethynyl)-N-(piperidin-3-yl)- 3-ureido thiophene-2-carboxamide ((S)-5-((3-fluorophenyl)ethynyl)-N-(piperidin-3-yl)-3-ureido thiophene-2-carboxamide).
- PHI-101 a compound represented by Formula 1 of the present invention, inhibits the proliferation of GIST-T1, a human GIST cell line. Since PHI-101 exhibits an IC 50 value of 36 nM in GIST-T1 cells, it may exhibit excellent gastrointestinal stromal tumor suppression activity.
- composition according to one embodiment of the present invention may be administered together with one or more anticancer agents.
- composition according to one embodiment of the present invention may be used alone or in combination with methods using surgery, hormone therapy, drug therapy, radiation therapy and/or biological response modifiers for the treatment of gastrointestinal stromal tumor. .
- the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in the manufacture of drugs, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin. , calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, etc. It is not limited.
- the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
- a lubricant e.g., a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
- Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington: the science and practice of pharmacy 22nd edition (2013).
- the pharmaceutical composition of the present invention may contain various bases and/or additives necessary and appropriate for the formulation of the dosage form, and nonionic surfactants, silicone polymers, extenders, fragrances, and preservatives within a range that does not impair the effect , disinfectant, oxidative stabilizer, organic solvent, ionic or nonionic thickener, emollient, antioxidant, free radical scavenger, opacifier, stabilizer, emollient, silicone, ⁇ -hydroxy acid, defoamer, humectant , vitamins, insect repellents, fragrances, preservatives, surfactants, anti-inflammatory agents, substance P antagonists, fillers, polymers, propellants, basifying or acidifying agents, or coloring agents.
- a suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity of the patient.
- the dosage of the pharmaceutical composition of the present invention may be 0.001 to 1000 mg/kg based on an adult.
- the pharmaceutical composition of the present invention may be administered orally or parenterally.
- the pharmaceutical composition of the present invention may be administered in various formulations upon oral administration, and may be administered in the form of tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, troches, etc. and may further include various excipients, for example, wetting agents, sweetening agents, fragrances, preservatives, and the like.
- the composition of the present invention when formulated as an oral dosage form, it may further include appropriate carriers, excipients and diluents commonly used in the preparation thereof.
- the carrier, excipient and diluent include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and/or mineral oil may be used, but are not limited thereto.
- it may be prepared by including diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. generally used for formulation, and may further include a lubricant such as magnesium stearate or talc in addition to the excipients. .
- the pharmaceutical composition of the present invention may be administered parenterally, for example, may be administered through methods such as subcutaneous injection, intravenous injection or intramuscular injection, but is not limited thereto.
- Formulation into a dosage form for parenteral administration may be, for example, preparing a solution or suspension by mixing the pharmaceutical composition of the present invention with water together with a stabilizer or buffer, and preparing it as an ampoule or vial unit dosage form.
- the composition is sterilized and may further include adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and buffers for regulating osmotic pressure, and other therapeutically useful substances, and is formulated by a conventional method.
- adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and buffers for regulating osmotic pressure, and other therapeutically useful substances.
- the gastrointestinal stromal tumor may be generated by substituting valine for aspartic acid, amino acid 816 constituting the c-kit protein.
- gastrointestinal stromal tumors 85 to 90% of gastrointestinal stromal tumors are caused by mutations in the KIT or PDGFR ⁇ gene, and among them, mutations in the KIT gene are the most common with a frequency of 75 to 80%. Since the compound represented by Formula 1 has excellent inhibitory activity against gastrointestinal stromal tumors having a mutation of aspartic acid, which is amino acid 816 constituting the c-kit protein, specifically, a mutation in which aspartic acid is substituted with valine, the gastrointestinal tract having such a mutation It can be usefully used for the prevention or treatment of stromal tumors.
- aspartic acid which is amino acid 816 constituting the c-kit protein
- Another aspect of the present invention provides a method for treating gastrointestinal stromal tumor comprising administering to a patient with a gastrointestinal stromal tumor a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the pharmaceutical composition according to one embodiment of the present invention contains the compound represented by Formula 1 as an active ingredient, and in particular, has excellent anticancer properties for gastrointestinal stromal tumors having a mutation of aspartic acid, amino acid 816 constituting the c-kit protein. show the effect. Therefore, prior to administering the pharmaceutical composition of the present invention, a companion diagnosis step of selecting a patient group showing an effect on the compound represented by Formula 1 may be further included, which is a gastrointestinal stromal tumor known in the art. It can be performed by the diagnostic method of
- the term "accompanying diagnosis” refers to a diagnosis for predicting a patient's response to a specific drug treatment in advance.
- Another aspect of the present invention provides a food composition for preventing or improving gastrointestinal stromal tumor comprising a compound represented by the following formula (1) or an acceptable salt thereof:
- the food composition of the present invention can be prepared by adding raw materials and ingredients commonly added in the art, and in addition to containing the compound represented by Chemical Formula 1 as an active ingredient, various flavoring agents or natural ingredients like conventional food compositions It may contain carbohydrates and the like as additional ingredients.
- natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.), disaccharides (eg, maltose, sucrose, etc.), and polysaccharides (eg, , dextrin, cyclodextrin, etc.) and sugar alcohols such as xylitol, sorbitol, and erythritol.
- the flavoring agent may include a natural flavoring agent (taumatine), a stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and/or a synthetic flavoring agent (saccharin, aspartame, etc.).
- the food composition of the present invention may be formulated as a food composition by including one or more pharmaceutically acceptable or pharmaceutically acceptable carriers in addition to the active ingredients described above.
- Formulations of the food composition may be tablets, capsules, powders, granules, liquids, pills, solutions, syrups, juices, suspensions, emulsions, or drops.
- the active ingredient may be combined with an orally, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
- the food composition of the present invention comprises a vitamin mixture comprising vitamin A acetate, vitamin E, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, biotin, nicotinic acid amide, folic acid, calcium pantothenate, and ferrous sulfate, zinc oxide , magnesium carbonate, potassium phosphate monobasic, potassium phosphate dibasic, potassium citrate, calcium carbonate and magnesium chloride, and the like, may include one or more minerals that can be added conventionally in the art.
- suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- the disintegrant may include starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
- These components may be used independently or in combination, and the proportion of these additives may be selected from 0 to about 20 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
- various foods can be prepared by applying the manufacturing method of various formulations known to those skilled in the art to the food composition of the present invention.
- the food composition of the present invention may be prepared in a conventional health functional food formulation such as beverage, pill, powder, etc., but is not limited thereto.
- the food composition of the present invention is particularly excellent in inhibiting proliferation of gastrointestinal stromal tumor cell lines, it can be usefully utilized for the prevention or improvement of gastrointestinal stromal tumors.
- Another aspect of the present invention is a method of treating a gastrointestinal stromal tumor comprising administering to a patient with a gastrointestinal stromal tumor a pharmaceutical composition comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to provide:
- Another aspect of the present invention provides the use of a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof for preventing or treating gastrointestinal stromal tumor:
- Another aspect of the present invention provides the use of a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for preventing or treating gastrointestinal stromal tumor:
- the inhibitory activity of the compound represented by Formula 1 (hereinafter referred to as 'PHI-101') against the c-kit mutant cell line was measured.
- the c-kit D816V mutant (FIG. 1) Ba/F3 cell line was adjusted to 10,000 cells/100 ⁇ l and put into a 96-well plate by 100 ⁇ l. After 4 hours, 100 ⁇ l of the Ba/F3 cell line was treated with 0.5 ⁇ l each of a control compound diluted by 10 points, 1/3 serial dilution, and PHI-101 to a final concentration of 50 ⁇ M, 5 % CO 2 Incubated for 72 hours at 37 °C condition. As control compounds, c-kit inhibitors Imatinib and Sunitinib were used. After incubation, the number of cells was measured using a Celltiter glo assay kit (Promega), and 50% growth inhibition values (GI 50 , ⁇ M) of the control compound and PHI-101 were measured.
- a control compound diluted by 10 points, 1/3 serial dilution, and PHI-101
- the c-kit phosphorylation and down-signaling inhibition (p-STAT3, p-ERK1/2) of the control compound and PHI-101 were measured.
- the control compound sunitinib and Dasatinib was used.
- the c-kit D816V mutant Ba/F3 cell line was aliquoted at a concentration of 1 ⁇ 10 6 cells/ml, and the control compound and PHI-101 were treated at concentrations of 0.1, 1, and 10 ⁇ M, respectively, and then cultured for 2 hours. Then, lysate the cells with lysis buffer (50 mM Tris-HCl pH7.5, 1% NP40, 1 mM EDTA, 150 mM NaCl, 5 mM, Na 3 VO 4 and 2.5 mM NaF, and protease inhibitor cocktail). seafood was obtained.
- lysis buffer 50 mM Tris-HCl pH7.5, 1% NP40, 1 mM EDTA, 150 mM NaCl, 5 mM, Na 3 VO 4 and 2.5 mM NaF, and protease inhibitor cocktail. seafood was obtained.
- the membrane was washed 3 times for 5 minutes with TBST (Tris-buffered saline, 0.1% Tween 20), and then diluted at a ratio of 1:10000 using HRP-binding anti-rabbit as a secondary antibody, and then at room temperature for 1 hour. After incubation, the cells were washed 3 times for 5 minutes with TBST, treated with a chemiluminescent substrate reagent, and the protein expression level was confirmed by detecting luminescence with a film in the dark.
- TBST Tris-buffered saline, 0.1% Tween 20
- c-kit D816V mutant Ba/F3 cell line was divided into 1 ⁇ 10 6 /ml concentration, PHI-101 was treated at 0.1, 1, 10 ⁇ M concentration, and sunitinib was treated as a control compound at 1, 10 ⁇ M concentration for 24 hours. . Then, the medium was removed and washed once with 1 ml PBS. The PBS was removed by centrifugation at 1000 rpm for 5 minutes. Cells were released with 100 ⁇ l of PBS containing Ca 2+ , Mg 2+ , and 5 ⁇ l Annexin V was added and reacted for 20 minutes.
- the SubG1/GO-1 population was analyzed through cell cycle FACS analysis.
- the c-kit D816V mutant Ba/F3 cell line was divided into 1 ⁇ 10 6 /ml concentration, and PHI-101 and a control compound, sunitinib, were treated at a concentration of 1 ⁇ M for 24 hours. After that, the medium was removed, and the c-kit D816V mutant Ba/F3 cell line was put in 70% ethanol and fixed at 4° C. for 24 hours, and then 40 ⁇ g/ml PI (propidium iodide) and 100 ⁇ g/ml RNase were mixed. Total DNA was stained by reaction in PBS buffer for 30 minutes. Cell cycle analysis of the stained cells was performed using a flow cytometer (FACS-C6, BD). The proportion of cells in the G0/G1 phase, S phase, and G2/M phase was measured, and based on this, the SubG1/GO-1 population was confirmed.
- FACS-C6, BD flow cytometer
- the inhibitory activity of PHI-101 against gastrointestinal stromal tumor (GIST) cell lines was measured.
- the GIST-T1 cell line was adjusted to 5,000 cells/100 ⁇ l and put into a 96-well plate by 100 ⁇ l. After stabilization for 24 hours, 100 ⁇ l of the GIST-T1 cell line was treated with 0.5 ⁇ l each of the control compound and PHI-101, which were serially diluted by 10 points and 1/3, so that the final concentration reached a maximum of 50 ⁇ M, Incubated for 72 hours at 37 °C conditions of 5% CO 2 .
- control compounds c-kit inhibitors imatinib, dasatinib, sunitinib and ponatinib were used. After incubation, the number of cells was measured using a Celltiter glo assay kit (Promega), and 50% growth inhibition values (GI 50 , ⁇ M) of the control compound and PHI-101 were measured.
- the c-kit phosphorylation and down-signaling inhibition (p-AKT, p-ERK1/2, p-S6) of the control compound and PHI-101 were measured, and the control compounds were imatinib and sunitinib. was used.
- the GIST-T1 cell line was treated with a control compound at a concentration of 1 ⁇ M and PHI-101 at a concentration of 0.01, 0.1, and 1 ⁇ M, and pc-kit Tyrosine 703 (Y703), p-AKT Threonine 308 (T308), as primary antibodies, Example 1-2, except that p-AKT Serine 473 (S473) Tyrosine 705 (Y705), p-ERK1/2 and p-S6 Serine 235/Serine 236 (S235/S236) were diluted at 1:3000 The ability to inhibit c-kit phosphorylation and sub-signal transduction was confirmed in the same manner as described above.
- Gastrointestinal stromal tumor cell lines were treated with PHI-101 to analyze the level of cleaved PARP, an apoptosis marker, and as control compounds, imatinib and sunitinib were used.
- the GIST-T1 cell line was treated with a control compound at a concentration of 1 ⁇ M and PHI-101 at a concentration of 0.01, 0.1, and 1 ⁇ M for 24 hours, and cleaved PARP as the primary antibody was diluted at 1:3000, except that it was used.
- the apoptosis effect of PHI-101 on the GIST-T1 cell line was analyzed in the same manner as in 1-2.
- mice were prepared as 6-8 week old NOD SCID female mice (18-22 g) (GemPharmatech Co., Ltd). Mice were acclimatized for 7 days before use in the experiment, and mice with abnormal health were excluded from the experiment. Mice were bred with a light-dark cycle of 12 hours in a cage (300 ⁇ 180 ⁇ 150mm) of 22 ⁇ 3° C. maintained at a relative humidity of 40% to 70%. Mice were allowed to freely ingest sterile dry granular food (Beijing Keaoxieli Feed Co., Ltd., Beijing, China) and water for the entire duration of the experiment except for the period specified in the protocol.
- c-kit D816V mutant Ba/F3 cells cultured in suspension in a 75T flask 50 ml of c-kit D816V mutant Ba/F3 cells cultured in suspension in a 75T flask were placed in a cone tube, centrifuged at 800 rpm for 2 minutes, and 2 minutes at 800 rpm with DPBS (Dulbecco's Phosphate-Buffered Saline, welgene) After washing by centrifugation for a minute, it was suspended in RPMI1640 (welgene) without antibiotics and fetal bovine serum (FBS). Then, it was stained with tryphan blue, and the number of cells was measured with a hematocytometer.
- DPBS Dynabecco's Phosphate-Buffered Saline, welgene
- the cell concentration was adjusted so that the number of viable cells was 1 ⁇ 10 7 cells/ml, and 100 ⁇ l of each was dispensed into an insulin syringe.
- the c-kit D816V Ba/F3 cell line was administered by tail vein administration.
- a xenograft mouse model was constructed.
- mice 3 days after transplantation of the c-kit D816V mutant Ba/F3 cell line, 6 mice were assigned to each group, and daily imatinib 90 mg/kg, sunitinib 20, 40 mg/kg, PHI-101 doses of 7, 20, 40, and 80 mg/kg were orally administered to mice, respectively.
- imatinib 90 mg/kg, sunitinib 20, 40 mg/kg, PHI-101 doses of 7, 20, 40, and 80 mg/kg were orally administered to mice, respectively.
- each compound was dissolved in 5% 1-methyl-2-pyrrolidone, and then thoroughly mixed in 15% Kolliphor, 30% PEG E400 HS15 and 50% 0.05M citric acid.
- the mouse weight is measured at intervals of 3 days after the start of oral administration of the drug to determine whether the body weight has changed. Confirmed.
- the condition of the mouse was checked and the dead subject was recorded. For each data, one-way ANOVA was used to test the significance of each group, and for the mouse life-span, a graph was derived using Kaplan Meier survival analysis, and the median survival time ) was found.
- PHI-101 had an effect of extending the survival period by 3 days compared to the vehicle administration group even at a low dose of 7 mg/kg, and in the 80 mg/kg administration group, the vehicle administration group It was confirmed that the survival period was extended by 2 times (FIG. 8).
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Abstract
Description
구분 | GI50(μM) | ||
PHI-101 | Imatinib | Sunitinib | |
cKIT D816V Ba/F3 | 0.912 | 11.48 | 2.647 |
Parental Ba/F3 | 5.010 | 12.73 | 13.32 |
구분 | GI50(μM) | ||||
PHI-101 | Imatinib | Dasatinib | Sunitinib | Ponatinib | |
GIST-T1 | 0.036 | 0.064 | 0.073 | 0.026 | - |
Claims (6)
- 제 1 항에 있어서, 상기 위장관기질종양은 c-kit 단백질을 구성하는 816번 아미노산인 아스파르트산(Aspartic acid)이 발린(Valine)으로 치환되어 발생하는 것인 위장관기질종양 예방 또는 치료용 약학적 조성물.
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