WO2023075062A1 - Composition for preventing or treating melanoma, comprising ac_774 - Google Patents
Composition for preventing or treating melanoma, comprising ac_774 Download PDFInfo
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- WO2023075062A1 WO2023075062A1 PCT/KR2022/008067 KR2022008067W WO2023075062A1 WO 2023075062 A1 WO2023075062 A1 WO 2023075062A1 KR 2022008067 W KR2022008067 W KR 2022008067W WO 2023075062 A1 WO2023075062 A1 WO 2023075062A1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- 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
-
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to a composition for preventing or treating melanoma containing AC_774.
- melanoma is a carcinoma derived from melanocytes that produce melanin pigment.
- Melanocytes derived from neural crest cells spread to various tissues of the body as well as skin and hair follicles, so melanoma is also common in most cases. Although it occurs in the skin, it can also be found in the eyes, mucous membranes, and central nervous system.
- the present invention provides a pharmaceutical composition for preventing or treating melanoma comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
- Another object of the present invention is to provide a health functional food composition for preventing or improving melanoma comprising a compound represented by Formula 1 below.
- Another object of the present invention is to provide a method for preventing or treating melanoma, comprising the step of administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject suspected of melanoma disease is in
- the present invention provides a pharmaceutical composition for preventing or treating melanoma comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a health functional food composition for preventing or improving melanoma comprising a compound represented by Formula 1 below.
- the present invention provides a method for preventing or treating melanoma, comprising administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject suspected of melanoma disease.
- a composition for preventing or treating melanoma comprising the compound represented by Formula 1 of the present invention, the present invention induces toxicity in melanoma cell lines and increases the infiltration of CD8-positive cytotoxic T cells in melanoma It has been confirmed and can be used to prevent, improve, and treat melanoma.
- FIG. 2 shows data obtained by treating melanoma cells with AC_774 at different concentrations, showing HIF-1 ⁇ , cell viability, and cytotoxicity according to AC_774 treatment.
- Figure 3 shows mice in groups treated with control, low concentration (10 mg/kg), medium concentration (30 mg/kg), and high concentration (60 mg/kg) that were not treated with AC_774 after inducing melanoma in nude mice. is a picture of them
- Figure 5 is the result data confirmed by TUNEL staining of melanoma and surrounding skin of a control group that was not treated with melanoma induced.
- Figure 6 is the result data confirmed by TUNEL staining of the melanoma and surrounding skin of the group treated with low concentration (10 mg/kg) after inducing melanoma.
- FIG. 10A shows the results of tissue immunofluorescence analysis of CD8 antibody rolls by paraffin-blocking tumors
- FIG. 10B is data showing the intensity of CD8 cells in 10A.
- One aspect is to provide a pharmaceutical composition for preventing or treating melanoma comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
- the compound represented by Formula 1 is 2-(4-((3r, 5r, 7r)-adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethane-1 -On, may be referred to as IDF-11774 or AC_774.
- the compound represented by Chemical Formula 1 is a hypoxiainducible factor-1 (HIF-1) inhibitor, which may alleviate melanoma by targeting Neuro, Inflammation, and Hypoxia.
- HIF-1 hypoxiainducible factor-1
- the compound represented by Chemical Formula 1 may inhibit HIF-1 ⁇ expression.
- the compound represented by Formula 1 is isolated from a natural source, obtained from a natural source and prepared by chemical modification, or easily chemically synthesized and prepared by a person skilled in the art by a known preparation method, or commercially produced. may be a product.
- salts of the compounds of the present invention refers to all salts (eg, obtained by reaction with an acid or base) of a compound of the present invention that is physiologically acceptable for a target animal (eg, mammal). Salts of the compounds of the present invention may be derived from organic or inorganic acids and bases.
- bases include, but are not limited to, alkali metal (eg, sodium) hydroxide, alkaline earth metal (eg, magnesium) hydroxide, and ammonia.
- salts include acetate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, malate, methanesulfonate , 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, thiocyanate, tosylate, undecanoate and the like including but not limited to Examples of other salts include Na + , NH 4+ , and NW 4+ (where W is an alkyl group of Cl to C4), and similar anions of compounds of the present invention
- the melanoma is a carcinoma derived from melanocytes that produce melanin pigment, and may be, for example, acrotic melanoma, nodular melanoma, superficial expansive melanoma, or malignant lentigo melanoma.
- prevention refers to all activities of suppressing or delaying the onset of melanoma by administering to a subject a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention.
- treatment means that the symptoms of melanoma are improved or benefited by administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention to a subject suspected of having cancer. It means any action that makes it happen.
- composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may further include a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier refers to a carrier or diluent that does not inhibit biological activities and properties of a compound to be administered without irritating living organisms.
- the type of the carrier that can be used in the present invention is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable can be used.
- Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. These may be used alone or in combination of two or more.
- additives such as antioxidants, buffers, and/or bacteriostatic agents may be added and used, and diluents, dispersants, surfactants, binders, and/or lubricants may be additionally added to form aqueous solutions, suspensions, emulsions, etc. It can be formulated into the same injection formulation, pill, capsule, granule or tablet and the like.
- a pharmaceutical composition for preventing or treating melanoma containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be prepared in various formulations according to a desired administration method.
- dosage forms for oral administration include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, and the like. can be heard
- a dosage form for oral administration such as a tablet or capsule
- lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin binders such as; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax.
- a liquid carrier such as fatty oil may be further included.
- parenteral administration of the composition for example, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, or local administration may be used, and a method of applying or spraying the composition to a diseased area may also be used. can, but is not limited to these.
- Formulations for parenteral administration include, for example, injectable forms such as subcutaneous injection, intravenous injection, or intramuscular injection; suppository injection method; Alternatively, it may be formulated for spraying such as an aerosol that enables inhalation through the respiratory tract, but is not limited thereto.
- the composition of the present invention may be mixed in water with a stabilizer or buffer to prepare a solution or suspension, which may be formulated for unit administration in an ampoule or vial.
- a propellant or the like may be blended with additives so that the water-dispersed concentrate or wet powder is dispersed.
- Another aspect is to provide a health functional food composition for preventing or improving melanoma comprising the compound represented by Formula 1.
- Another aspect provides a method for preventing or treating melanoma, comprising administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject suspected of melanoma disease.
- the method for preventing or treating melanoma of the present invention comprises administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount to a subject who has or is at risk of developing melanoma. It includes steps to A suitable daily total amount of the composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be appropriately determined by a person skilled in the art within the scope of sound medical judgment.
- the administration route and administration method for administering the composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof are not particularly limited, and the desired site is treated with Formula 1 Any administration route and administration method can be followed as long as the composition containing the indicated compound or its pharmaceutically acceptable salt can be reached.
- the composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered through various routes, either oral or parenteral, and non-limiting examples of the route of administration include oral, rectal, and those administered through topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, intranasal, or inhalation.
- the composition may down-regulate the expression of one or more proteins selected from the group consisting of N-cadherin, vimentin, fibronectin and SNAIL, but is not limited thereto.
- Another aspect is to provide a pharmaceutical composition for preventing or treating melanoma metastasis with increased expression of N-cadherin, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient do.
- Cytotoxicity was evaluated by lactate dehydrogenase (LDH) release method.
- LDH activity was measured in the culture medium using a cytotoxicity detection kit (Roche, Penzberg, Germany).
- LDH release in the supernatant of the experimental culture was determined by measuring the optical density at 490 nm and then subtracting the optical density at 620 nm.
- the effect of chemicals on cytotoxicity was calculated as the ratio of LDH release of each chemical to an appropriate solvent.
- the melanoma cell line B16F10 purchased from the Korean Cell Line Bank was cultured in DMEM medium. 200,000 and 500,000 of the cultured cell lines were respectively suspended in 100 ⁇ L of HBS buffer and injected subcutaneously into the lower abdomen of a nude mouse according to each concentration. Two experimental mice were used for each concentration. The presence or absence of tumor formation was checked at intervals of one week, and the size was measured. The size of the tumor was observed until the size of the tumor reached 1 cm ⁇ 1 cm ⁇ 1 cm in width ⁇ length ⁇ height, and the experiment was performed by selecting the concentration of cells that reached the desired size in a short time.
- Example 1 Comparison of HLF-1 ⁇ expression inhibition, cell viability, and cytotoxicity in normal melanocytes and melanoma cells according to AC_774 treatment
- the survival rate was 70% up to 5 ⁇ M, whereas the survival rate was significantly decreased from 7 ⁇ M.
- the decrease in survival rate was small until 1.25 ⁇ M, but there was a significant decrease in survival rate from 2.5 ⁇ M. Cytotoxicity was also significantly increased from 2.5 ⁇ M, and it was confirmed that it significantly increased from 1.25 ⁇ M in a hypoxic environment.
- AC_774 exhibits toxicity against melanoma under a hypoxic environment at a lower concentration than in a non-hypoxic environment.
- Example 2-1 Determination of concentration inducing melanoma in nude mice
- the size of the biopsied tumor was calculated using the formula 1/2LW 2 (L: tumor length, W: tumor width).
- L tumor length
- W tumor width
- the tumor size was measured except for one animal with a difference in tumor size for each group, and the medium concentration (30mg / kg) and high concentration (60mg / kg) treatment group significantly decreased compared to the untreated group. confirmed that.
- CD8-positive cytotoxic T cells were mainly observed in the tumor, and the intensity of fluorescence staining was significantly increased in the AC_774-administered group compared to the non-administered group as shown in the graph, and was higher in the high-concentration-administered group than in the medium-concentration-administered group. Therefore, it showed a concentration-dependent tendency.
- the high concentration administration group spaces that appeared to be caused by cell loss were observed in the tumor area where T cells were clustered.
- epithelial-mesenchymal transition is one of the main mechanisms of metastasis.
- Epithelial markers such as cytokeratin, E cadherin and occludin are downregulated, whereas mesenchymal markers such as N-cadherin, vimentin and fibronectin are upregulated in EMT.
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Abstract
The present invention relates to a composition for preventing or treating melanoma, comprising a compound represented by chemical formula 1. In the present invention, the effects of inducing toxicity, reducing the size of melanoma, increasing the infiltration of CD8+ cytotoxic T cells into melanoma, and inhibiting the metastasis of melanoma have been identified in melanoma cell lines, and thus the present invent can be used in the prevention, alleviation and treatment of melanoma or melanoma metastasis.
Description
본 발명은 AC_774를 포함하는 흑색종 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating melanoma containing AC_774.
암을 재발 없이 극복한 사람들의 경험과 연구 결과들로부터 암을 관해하는 표적으로 신경(Neuro), 염증(Inflammation), 저산소(Hypoxia)를 도출할 수 있으며, 이 세가지(NIH) 요인을 제어할 수 있는 물질을 도출하여 병용투여법 또는 복합제로 개발하므로 단독 또는 면역관련 의약품과의 병용투여를 통해 암을 관해하고자 하는 많은 연구가 진행중이다. From the experiences and research results of people who have overcome cancer without recurrence, it is possible to derive Neuro, Inflammation, and Hypoxia as targets for remission of cancer, and these three (NIH) factors can be controlled. Many studies are underway to cure cancer through single or combined administration with immune-related medicines.
암 중 흑색종은 멜라닌 색소를 생산하는 멜라닌 세포로부터 유래된 암종으로, 신경능세포(neural crest cell)에서 유래된 멜라닌 세포는 피부와 모낭뿐만 아니라 신체의 다양한 조직에 퍼져 있어 흑색종 역시 대부분의 경우 피부에서 발생하지만, 안구, 점막, 중추신경계 등에서도 발견될 수 있다. Among cancers, melanoma is a carcinoma derived from melanocytes that produce melanin pigment. Melanocytes derived from neural crest cells spread to various tissues of the body as well as skin and hair follicles, so melanoma is also common in most cases. Although it occurs in the skin, it can also be found in the eyes, mucous membranes, and central nervous system.
이러한 흑색종은 피부암 사례의 2% 미만이지만 피부암 사망의 대부분을 차지하며, 조기 발견과 치료가 이루어지지 않을 경우 전이로 이어질 수 있다. 또한, 전이된 후에는 치료하기가 훨씬 더 어려워진다. 전이가 어디로 되었는지, 얼마나 되었는지에 따라 치료는 화학요법, 수술, 유전자요법, 면역요법, 방사선요법 및 이의 조합을 포함하여 할 수 있다. 최근 면역기전에 근거하여 개발한 항암제를 통하여 괄목할만한 발전을 이루었으나, 아직은 치료율이 저조하여 새로운 치료제 연구가 지속적으로 요구되고 있는 실정이다.Although these melanomas account for less than 2% of skin cancer cases, they account for the majority of skin cancer deaths and can lead to metastasis if not detected and treated early. Also, once it has metastasized, it becomes much more difficult to treat. Depending on where the metastases have been and how old, treatment may include chemotherapy, surgery, gene therapy, immunotherapy, radiation therapy, and combinations thereof. Recently, remarkable progress has been made through anticancer drugs developed based on immune mechanisms, but the treatment rate is still low, so research on new treatments is continuously required.
본 발명의 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표기되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating melanoma comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
본 발명의 또 다른 목적은 하기 화학식 1로 표기되는 화합물을 포함하는 흑색종 예방 또는 개선용 건강기능식품 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a health functional food composition for preventing or improving melanoma comprising a compound represented by Formula 1 below.
[화학식 1][Formula 1]
본 발명의 다른 목적은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는 조성물을 흑색종 질환 의심 개체에 투여하는 단계를 포함하는 흑색종 예방 또는 치료 방법을 제공하는 데에 있다.Another object of the present invention is to provide a method for preventing or treating melanoma, comprising the step of administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject suspected of melanoma disease is in
본 발명의 또 다른 목적은 하기 화학식 1로 표시되는 화합물 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 전이 예방 또는 치료용 약학적 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating melanoma metastasis comprising a compound represented by Formula 1 below and a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
본 발명의 또 다른 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, N-카드헤린(N-cadherin) 발현이 증가된 흑색종 전이 예방 또는 치료용 약학적 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a pharmaceutical for preventing or treating melanoma metastasis with increased expression of N-cadherin, comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide an enemy composition.
[화학식 1] [Formula 1]
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표기되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating melanoma comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
또한, 본 발명은 하기 화학식 1로 표기되는 화합물을 포함하는 흑색종 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving melanoma comprising a compound represented by Formula 1 below.
[화학식 1][Formula 1]
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물을 흑색종 질환 의심 개체에 투여하는 단계를 포함하는 흑색종 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method for preventing or treating melanoma, comprising administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject suspected of melanoma disease.
또한, 본 발명은 하기 화학식 1로 표시되는 화합물 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 전이 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating melanoma metastasis comprising a compound represented by Formula 1 below and a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
또한, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, N-카드헤린(N-cadherin) 발현이 증가된 흑색종 전이 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating melanoma metastasis with increased expression of N-cadherin, comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient provides
[화학식 1] [Formula 1]
본 발명의 화학식 1로 표기되는 화합물을 포함하는 흑색종 예방 또는 치료용 조성물에 대한 것으로, 본 발명은 흑색종 세포주에서 독성을 유발하며, 흑색종 내 CD8양성 세포독성 T 세포의 침윤을 증가시킴을 확인하였으며 이를 이용하여 흑색종을 예방, 개선 및 치료에 활용할 수 있다.A composition for preventing or treating melanoma comprising the compound represented by Formula 1 of the present invention, the present invention induces toxicity in melanoma cell lines and increases the infiltration of CD8-positive cytotoxic T cells in melanoma It has been confirmed and can be used to prevent, improve, and treat melanoma.
도 1은 AC_774를 정상인의 멜라닌 세포에 농도별로 처리한 결과 데이터로, A는 세포 생존율을 확인한 데이터, B는 세포독성을 확인한 데이터, C는 S100B의 내부 농도를 확인한 데이터, 및 D는 S100B의 외부 농도를 확인한 데이터이다. Figure 1 is the result data of AC_774 treated melanocytes of normal people by concentration, A is data confirming cell viability, B is data confirming cytotoxicity, C is data confirming the internal concentration of S100B, and D is data confirming the external concentration of S100B This is the data confirming the concentration.
도 2는 AC_774를 흑색종 세포에 농도별로 처리한 결과 데이터로, AC_774처리에 따른, HIF-1α, 세포 생존율 및 세포독성을 확인한 데이터이다. FIG. 2 shows data obtained by treating melanoma cells with AC_774 at different concentrations, showing HIF-1α, cell viability, and cytotoxicity according to AC_774 treatment.
도 3은 흑색종을 nude mouse에 유발시킨 후, AC_774를 처리하지 않은 대조군, 저농도(10 mg/kg), 중농도(30 mg/kg) 및 고농도(60 mg/kg)로 처리한 군들의 마우스들의 사진이다.Figure 3 shows mice in groups treated with control, low concentration (10 mg/kg), medium concentration (30 mg/kg), and high concentration (60 mg/kg) that were not treated with AC_774 after inducing melanoma in nude mice. is a picture of them
도 4는 AC_774를 처리하지 않은 대조군, 저농도(10 mg/kg), 중농도(30 mg/kg) 및 고농도(60 mg/kg)로 처리하였을 때, 일(days) 수 에 따른 흑색종의 유발 정도(크기)를 확인한 데이터이다. Figure 4 shows the induction of melanoma according to the number of days when AC_774 was treated with untreated control, low concentration (10 mg/kg), medium concentration (30 mg/kg), and high concentration (60 mg/kg) It is the data that confirmed the degree (size).
도 5는 흑색종을 유발시키고 치료하지 않은 대조군의 흑색종 및 주변 피부를 TUNEL 염색하여 확인한 결과데이터이다. Figure 5 is the result data confirmed by TUNEL staining of melanoma and surrounding skin of a control group that was not treated with melanoma induced.
도 6은 흑색종을 유발시키고 저농도 (10mg/kg)을 처리한 군의 흑색종 및 주변 피부를 TUNEL 염색하여 확인한 결과데이터이다.Figure 6 is the result data confirmed by TUNEL staining of the melanoma and surrounding skin of the group treated with low concentration (10 mg/kg) after inducing melanoma.
도 7은 흑색종을 유발시키고 중농도 (30mg/kg)을 처리한 군의 흑색종 및 주변 피부를 TUNEL 염색하여 확인한 결과데이터이다.7 shows the result data confirmed by TUNEL staining of the melanoma and the surrounding skin of the group treated with medium concentration (30 mg/kg) after inducing melanoma.
도 8은 흑색종을 유발시키고 고농도 (60mg/kg)을 처리한 군의 흑색종 및 주변 피부를 TUNEL 염색하여 확인한 결과데이터이다.8 shows the result data confirmed by TUNEL staining of the melanoma and surrounding skin of a group treated with a high concentration (60 mg/kg) after inducing melanoma.
도 9는 흑색종을 유발시키고 치료하지 않은 대조군, 저농도 (10mg/kg), 중농도 (30mg/kg) 및 고농도 (60mg/kg)를 처리한 군의 세포사멸 정도를 확인한 그래프이다.Figure 9 is a graph confirming the degree of apoptosis in the control group, low concentration (10mg / kg), medium concentration (30mg / kg) and high concentration (60mg / kg) treatment group that induces melanoma and is not treated.
도 10A는 종양을 파라핀 블록으로 만들어 CD8 항체롤 조직면역형광검사를 한 결과를 나타내는 것이고, 10B는 10A의 CD8 세포의 강도를 나타낸 데이터이다.FIG. 10A shows the results of tissue immunofluorescence analysis of CD8 antibody rolls by paraffin-blocking tumors, and FIG. 10B is data showing the intensity of CD8 cells in 10A.
도 11는 B16F10 흑색종 세포에 CoCl2 처리하고 AC_774를 처리함에 따른 HIF-1α 발현량 변화, 저산소 환경에서의 cyclin D1의 발현량 변화 및 종양에서의 활성-caspase3의 발현량 변화를 확인한 데이터이다.11 is data confirming changes in HIF-1α expression levels, changes in cyclin D1 expression levels, and active-caspase3 expression levels in tumors in B16F10 melanoma cells treated with CoCl 2 and AC_774.
도 12은 AC_774를 처리에 따른 B16F10 흑색종 세포의 성장억제 및 전이 억제효과를 확인하기 위해서 N-cadherin, E-cadherin 및 SNAIL 단백질의 발현변화를 확인한 데이터이다.12 is data confirming the expression changes of N-cadherin, E-cadherin, and SNAIL proteins in order to confirm the effect of inhibiting growth and metastasis of B16F10 melanoma cells according to AC_774 treatment.
일 양상은 하기 화학식 1로 표기되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 예방 또는 치료용 약학적 조성물을 제공하는 것이다. One aspect is to provide a pharmaceutical composition for preventing or treating melanoma comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 화학식 1로 표기되는 화합물은 2-(4-((3r, 5r, 7r)-아다만탄-1-일)페녹시)-1-(4-메틸피페라진-1-일)에탄-1-온, IDF-11774 또는 AC_774로 일컬을 수 있다.The compound represented by Formula 1 is 2-(4-((3r, 5r, 7r)-adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethane-1 -On, may be referred to as IDF-11774 or AC_774.
상기 화학식 1로 표기되는 화합물은 hypoxiainducible factor-1(HIF-1) 저해제로, 신경(Neuro), 염증(Inflammation), 저산소(hypoxia)를 표적으로 하여 흑색종을 완화시키는 것일 수 있다. The compound represented by Chemical Formula 1 is a hypoxiainducible factor-1 (HIF-1) inhibitor, which may alleviate melanoma by targeting Neuro, Inflammation, and Hypoxia.
상기 화학식 1로 표기되는 화합물은 HIF-1α 발현을 억제하는 것일 수 있다.The compound represented by Chemical Formula 1 may inhibit HIF-1α expression.
상기 화학식 1로 표기되는 화합물은 천연 공급원으로부터 분리되거나, 천연 공급원으로부터 수득하여 화학적인 개질에 의해 제조하고나, 또는 공지의 제조방법에 의해 당업자가 용이하게 화학적으로 합성하여 제조하거나, 상업적으로 제조된 상품일 수 있다.The compound represented by Formula 1 is isolated from a natural source, obtained from a natural source and prepared by chemical modification, or easily chemically synthesized and prepared by a person skilled in the art by a known preparation method, or commercially produced. may be a product.
본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물에 있어서, 상기 화학식 1로 표시되는 화합물의 농도는 상기 조성물이 흑색종 예방 또는 치료의 효능을 충분히 나타내는 정도라면 특별히 제한되지 아니하나, 예를 들면 상기 조성물의 부피를 기준으로, 1μM 내지 100μM, 1μM 내지 20μM 일 수 있으나, 이에 제한되지 않는다. 참고로 상기 화학식 1로 표시되는 화합물의 농도 범위에서 사용된 M은 몰농도를 나타낸 것이며, 몰농도는 용액 1리터중에 녹아 있는 용질의 몰(mol) 수를 의미한다. In the composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention, the concentration of the compound represented by Formula 1 is such that the composition sufficiently exhibits efficacy in preventing or treating melanoma. It is not particularly limited, but may be, for example, 1 μM to 100 μM, 1 μM to 20 μM based on the volume of the composition, but is not limited thereto. For reference, M used in the concentration range of the compound represented by Formula 1 represents the molarity, and the molarity means the number of moles (mol) of the solute dissolved in 1 liter of the solution.
본 발명에서 사용되는 용어 "약학적으로 허용 가능한 염"은 표적 동물 (예컨대, 포유류)이 생리학적으로 수인 가능한 본 발명의 화합물의 모든 (예컨대, 산 또는 염기와 반응하여 얻은) 염을 의미한다. 본 발명 화합물의 염은 유기 또는 무기산 및 염기로부터 유도될 수 있다. 산의 예로서는 질산, 과염소산, 푸마르산, 말레산, 인산, 글리콜산, 락트산, 살리실산, 숙신산, 톨루엔-p-황산, 아세트산, 시트르산, 에탄설폰산, 벤조산, 말론산, 설폰산, 벤젠설폰산 등이 포함되나 이에 한정되지 않는다. 그 자체로는 약학적으로 허용할 수 없지만 옥살산 등의 그 밖의 산 또한 본 발명의 화합물 및 이들의 약학적으로 허용 가능한 첨가염을 획득하기 위한 중간체로서 유용한 염의 제조시 사용될 수 있다. 염기의 예에는 알칼리 금속 (예컨대, 나트륨) 수산화물, 알칼리 토금속 (예컨대, 마그네슘) 수산화물, 및 암모니아를 포함하나 이에 한정되지 않는다. 염의 예에는 아세테이트, 플루코헵타노에이트, 글리세로포스페이트, 헤미설페이트, 헵타노에이트, 헥사노에이트, 클로라이드, 브로마이드, 아이오다이드, 2-하이드록시에탄설포네이트, 락테이트, 말레이트, 메탄설포네이트, 2-나프탈렌설포네이트, 옥살레이트, 파모에이트, 펙티네이트, 퍼설페이트, 페닐프로피오네이트, 피크레이트, 피발레이트, 프로피오네이트, 숙시네이트, 티오시아네이트, 토실레이트, 운데카노에이트 및 이와 유사한 것을 포함하나 이에 한정되지 않는다. 그 밖의 염의 예에는 Na+, NH4+, 및 NW4+ (여기서 W는 Cl 내지 C4의 알킬기이다), 및 이와 유사한 적절한 양이온과 화합하는 본 발명 화합물의 음이온이 포함된다. 치료용으로 사용되기 위하여, 본 발명 화합물의 염은 약학적으로 허용 가능하도록 고려되었다. 그러나 약학적으로 허용 불가능한 산 및 염기의 염도 예컨대, 약학적으로 허용 가능한 화합물의 제조 또는 정제에 사용될 수 있다. As used herein, the term "pharmaceutically acceptable salt" refers to all salts (eg, obtained by reaction with an acid or base) of a compound of the present invention that is physiologically acceptable for a target animal (eg, mammal). Salts of the compounds of the present invention may be derived from organic or inorganic acids and bases. Examples of acids include nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfuric acid, acetic acid, citric acid, ethanesulfonic acid, benzoic acid, malonic acid, sulfonic acid, benzenesulfonic acid, and the like. Including, but not limited to. Although not pharmaceutically acceptable per se, other acids such as oxalic acid may also be used in the preparation of salts useful as intermediates for obtaining the compounds of the present invention and their pharmaceutically acceptable addition salts. Examples of bases include, but are not limited to, alkali metal (eg, sodium) hydroxide, alkaline earth metal (eg, magnesium) hydroxide, and ammonia. Examples of salts include acetate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, malate, methanesulfonate , 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, thiocyanate, tosylate, undecanoate and the like including but not limited to Examples of other salts include Na + , NH 4+ , and NW 4+ (where W is an alkyl group of Cl to C4), and similar anions of compounds of the present invention that combine with suitable cations. For therapeutic use, salts of the compounds of the present invention are considered pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.
상기 흑색종은 멜라닌 색소를 생산하는 멜라닌 세포로부터 유래된 암종으로, 예를 들면, 선단 흑색점성 흑색종, 결절성 흑색종, 표재 확장성 흑색종, 악성 흑색점 흑색종일 수 있다. The melanoma is a carcinoma derived from melanocytes that produce melanin pigment, and may be, for example, acrotic melanoma, nodular melanoma, superficial expansive melanoma, or malignant lentigo melanoma.
본 발명에서 사용되는 용어 "예방" 이란, 본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물을 개체에 투여하여 흑색종의 발병을 억제시키거나 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" refers to all activities of suppressing or delaying the onset of melanoma by administering to a subject a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention. means
본 발명에서 사용되는 용어 "치료"란, 본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물을 암 발병 의심 개체에 투여하여 흑색종의 증세가 호전되도록 하거나 이롭게 되도록 하는 모든 행위를 의미한다.As used herein, the term "treatment" means that the symptoms of melanoma are improved or benefited by administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention to a subject suspected of having cancer. It means any action that makes it happen.
본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물은 약학적으로 허용 가능한 담체를 추가로 포함할 수 있다. 상기 "약학적으로 허용 가능한 담체"란 생물체를 자극하지 않으면서, 투여되는 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 의미한다.The composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may further include a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not inhibit biological activities and properties of a compound to be administered without irritating living organisms.
본 발명에 사용 가능한 상기 담체의 종류는 특별히 제한되지 아니하며 당해 기술 분야에서 통상적으로 사용되고 약학적으로 허용되는 담체라면 어느 것이든 사용할 수 있다. 상기 담체의 비제한적인 예로는, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사 용액, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올 등을 들 수 있다. 이들은 단독으로 사용되거나 2 종 이상을 혼합하여 사용될 수 있다 The type of the carrier that can be used in the present invention is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable can be used. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. These may be used alone or in combination of two or more.
또한, 필요한 경우 항산화제, 완충액 및/또는 정균제 등 다른 통상의 첨가제를 첨가하여 사용할 수 있으며, 희석제, 분산제, 계면 활성제, 결합제 및/또는 윤활제 등을 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제 등으로 제제화하여 사용할 수 있다.In addition, if necessary, other conventional additives such as antioxidants, buffers, and/or bacteriostatic agents may be added and used, and diluents, dispersants, surfactants, binders, and/or lubricants may be additionally added to form aqueous solutions, suspensions, emulsions, etc. It can be formulated into the same injection formulation, pill, capsule, granule or tablet and the like.
본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 흑색종의 예방 또는 치료용 약학적 조성물의 투여 방식은 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용하는 방식에 따를 수 있다. 상기 투여 방식의 비제한적인 예로, 조성물을 경구 투여 또는 비경구 투여 방식으로 투여할 수 있다.The method of administering the pharmaceutical composition for preventing or treating melanoma comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention is not particularly limited, and is a method commonly used in the art. can follow As a non-limiting example of the administration method, the composition may be administered by oral administration or parenteral administration.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 흑색종의 예방 또는 치료용 약학적 조성물은 목적하는 투여 방식에 따라 다양한 제형으로 제작될 수 있다. 경구 투여용 제형의 비제한적인 예로는, 트로키제 (troches), 로젠지 (lozenge), 정제, 수용성 현탁액, 유성 현탁액, 조제 분말, 과립, 에멀젼, 하드 캡슐, 소프트 캡슐, 시럽 또는 엘릭시르제 등을 들 수 있다. A pharmaceutical composition for preventing or treating melanoma containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be prepared in various formulations according to a desired administration method. Non-limiting examples of dosage forms for oral administration include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs, and the like. can be heard
상기 조성물을 정제 또는 캡슐 등과 같은 경구 투여용 제형으로 제제화하기 위하여, 락토오스, 사카로오스 (Saccharose), 솔비톨 (Sorbitol), 만니톨 (Mannitol), 전분, 아밀로펙틴 (Amylopectin), 셀룰로오스 (Cellulose) 또는 젤라틴 (Gelatin) 등과 같은 결합제; 디칼슘 포스페이트 (dicalcium phosphate) 등과 같은 부형제; 옥수수 전분 또는 고구마 전분 등과 같은 붕괴제; 스테아르산 마그네슘 (magnesium stearate), 스테아르산 칼슘 (calcium stearate), 스테아릴 푸마르산 나트륨 (sodium stearyl fumarate) 또는 폴리에틸렌 글리콜왁스 (polyethylene glycol wax) 등과 같은 윤활유 등을 포함할 수 있다. 나아가 캡슐 제형의 경우 상기 언급한 물질 외에도 지방유와 같은 액체 담체 등을 추가로 함유할 수 있다. In order to formulate the composition into a dosage form for oral administration such as a tablet or capsule, lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin binders such as; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax. Furthermore, in the case of a capsule formulation, in addition to the above-mentioned substances, a liquid carrier such as fatty oil may be further included.
상기 조성물을 비경구 투여하는 방법으로는, 예를 들어 정맥 내 투여, 복강 내 투여, 근육 내 투여, 피하 투여 또는 국부 투여 등을 이용할 수 있으며, 상기 조성물을 질환 부위에 도포하거나 분무하는 방법 또한 이용할 수 있으나 이들에 제한되지 아니한다. As a method of parenteral administration of the composition, for example, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, or local administration may be used, and a method of applying or spraying the composition to a diseased area may also be used. can, but is not limited to these.
상기 비경구 투여를 위한 제형으로는, 예를 들어 피하 주사, 정맥 주사 또는 근육 내 주사 등의 주사용 형태; 좌제 주입 방식; 또는 호흡기를 통하여 흡입이 가능하도록 하는 에어로졸제 등 스프레이용으로 제제화할 수 있으나 이에 제한되지 아니한다. 상기 주사용 제형으로 제제화하기 위해서는 본 발명의 조성물을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고 이를 앰플 (ampoule) 또는 바이알 (vial)의 단위 투여용으로 제제화할 수 있다. 상기 에어로졸제 등의 스프레이용으로 제형화하는 경우, 수분산된 농축물 또는 습윤 분말이 분산되도록 추진제 등이 첨가제와 함께 배합될 수 있다.Formulations for parenteral administration include, for example, injectable forms such as subcutaneous injection, intravenous injection, or intramuscular injection; suppository injection method; Alternatively, it may be formulated for spraying such as an aerosol that enables inhalation through the respiratory tract, but is not limited thereto. In order to formulate the formulation for injection, the composition of the present invention may be mixed in water with a stabilizer or buffer to prepare a solution or suspension, which may be formulated for unit administration in an ampoule or vial. When formulated for spraying such as the aerosol, a propellant or the like may be blended with additives so that the water-dispersed concentrate or wet powder is dispersed.
본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 흑색종의 예방 또는 치료용 약학적 조성물의 적합한 도포, 분무 또는 투여량은, 상기 조성물의 제제화 방법, 투여 방식, 투여 시간 및/또는 투여 경로는 물론, 투여 대상이 되는 동물의 나이, 체중, 성별, 질병 증상의 정도, 섭취하는 음식, 배설 속도 등과 같은 요인들에 의해 다양해 질 수 있으며, 당해 기술 분야에서 통상의 지식을 가진 자는 목적하는 치료에 효과적인 투여량을 용이하게 결정하고 처방할 수 있다.Appropriate application, spraying or dosage of the pharmaceutical composition for the prevention or treatment of melanoma comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention, the formulation method of the composition, the method of administration, The administration time and/or route of administration may vary depending on factors such as the age, weight, sex, degree of disease symptoms, food consumed, and excretion rate of the animal to be administered, as well as conventional methods in the art. A knowledgeable person can readily determine and prescribe dosages effective for the desired treatment.
또 다른 양상은 화학식 1로 표기되는 화합물을 포함하는 흑색종 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다. Another aspect is to provide a health functional food composition for preventing or improving melanoma comprising the compound represented by Formula 1.
[화학식 1] [Formula 1]
상기 화학식1로 표기되는 화합물, 흑색종, 예방, 개선, 및 식품 조성물에 관한 것은 상기 기재된 것과 동일하다.The compounds represented by Formula 1, melanoma, prevention, improvement, and food compositions are the same as those described above.
본 발명에서 사용되는 용어, "건강기능식품"은 건강보조의 목적으로 특정성분을 원료로하거나 식품 원료에 들어있는 특정성분을 추출, 농축, 정제, 혼합 등의 방법으로 제조, 가공한 식품을 말하며, 상기 성분에 의해 생체방어, 생체리듬의 조절, 질병의 방지와 회복 등 생체조절기능을 생체에 대하여 충분히 발휘할 수 있도록 설계되고 가공된 식품을 말하는 것으로서, 상기 건강식품용 조성물은 질병의 예방 및 질병의 회복 등과 관련된 기능을 수행할 수 있다.As used in the present invention, the term "health functional food" refers to food manufactured and processed by using specific ingredients as raw materials or by extracting, concentrating, refining, mixing, etc. specific ingredients contained in food ingredients for the purpose of health supplementation , It refers to a food designed and processed to sufficiently exert bioregulatory functions such as biodefense, regulation of biorhythm, prevention and recovery of disease, etc. with respect to the living body by the above components, and the composition for health food is used to prevent disease and prevent disease. It can perform functions related to recovery of
다른 양상은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는 조성물을 흑색종 질환 의심 개체에 투여하는 단계를 포함하는 흑색종 예방 또는 치료 방법을 제공한다.Another aspect provides a method for preventing or treating melanoma, comprising administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject suspected of melanoma disease.
본 발명에서 사용되는 용어 " 흑색종 질환 의심 개체"란, 흑색종이 발병되었거나 발병할 가능성이 있는 인간을 포함한 모든 동물을 의미한다.As used herein, the term "subject suspected of melanoma disease" refers to all animals, including humans, that have or may have melanoma.
본 발명의 상기 예방 또는 치료 방법은 구체적으로, 흑색종이 발병하였거나 발병할 위험이 있는 개체에 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함한다. 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물의 적합한 1 일 총 사용량은 올바른 의학적 판단 범위 내에서 당업자에 의해 적절하게 결정될 수 있다.Specifically, the method for preventing or treating melanoma of the present invention comprises administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount to a subject who has or is at risk of developing melanoma. It includes steps to A suitable daily total amount of the composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be appropriately determined by a person skilled in the art within the scope of sound medical judgment.
특정 동물에 대한 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물의 구체적인 약학적 유효량은, 달성하고자 하는 반응의 종류와 정도, 해당 개체의 연령, 체중, 일반적인 건강 상태, 성별 또는 식이는 물론, 상기 화학식 1로 표시되는 화합물을 유효 성분으로 포함하는 조성물의 투여 시간, 투여 경로 및 조성물의 분비율, 치료 기간 등을 고려하여 결정될 수 있으며, 동시 또는 이시에 함께 사용되는 약물 기타 조성물의 성분 등을 비롯한 여러 인자 및 의약 분야에서 잘 알려진 유사 인자에 따라 다양해질 수 있다.A specific pharmaceutically effective amount of a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for a specific animal is the type and degree of response to be achieved, the age, weight, general health condition of the subject, It can be determined in consideration of sex or diet, as well as the administration time of the composition containing the compound represented by Formula 1 as an active ingredient, the route of administration and the secretion rate of the composition, the treatment period, etc., and drugs used simultaneously or simultaneously It may vary according to several factors, including other components of the composition, and like factors well known in the medical arts.
본 발명의 상기 예방 또는 치료 방법에서 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물을 투여하는 투여 경로 및 투여 방식은 특별히 제한되지 아니하며 목적하는 해당 부위에 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물이 도달할 수 있는 한 임의의 투여 경로 및 투여 방식에 따를 수 있다. 구체적으로, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 조성물은 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있으며, 그 투여 경로의 비제한적인 예로는, 구강, 직장, 국소, 정맥내, 복강내, 근육내, 동맥내, 경피, 비측내 또는 흡입 등을 통하여 투여되는 것을 들 수 있다.In the prevention or treatment method of the present invention, the administration route and administration method for administering the composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof are not particularly limited, and the desired site is treated with Formula 1 Any administration route and administration method can be followed as long as the composition containing the indicated compound or its pharmaceutically acceptable salt can be reached. Specifically, the composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered through various routes, either oral or parenteral, and non-limiting examples of the route of administration include oral, rectal, and those administered through topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, intranasal, or inhalation.
다른 양상은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 전이 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for preventing or treating melanoma metastasis comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1] [Formula 1]
상기 조성물은 N-cadherin, vimentin, fibronectin 및 SNAIL로 이루어진 군에서 선택된 하나 이상의 단백질 발현을 하향조절할 수 있으나, 이에 한정되는 것은 아니다.The composition may down-regulate the expression of one or more proteins selected from the group consisting of N-cadherin, vimentin, fibronectin and SNAIL, but is not limited thereto.
상기 조성물은 cytokeratin, E cadherin 및 occludin로 이루어진 군에서 선택된 하나 이상의 단백질 발현을 상항조절할 수 있으나, 이에 한정되는 것은 아니다.The composition may up-regulate the expression of one or more proteins selected from the group consisting of cytokeratin, E-cadherin and occludin, but is not limited thereto.
다른 양상은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, N-카드헤린(N-cadherin) 발현이 증가된 흑색종 전이 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect is to provide a pharmaceutical composition for preventing or treating melanoma metastasis with increased expression of N-cadherin, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient do.
[화학식 1] [Formula 1]
이하 하나 이상의 구체예를 실시예를 통해 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are intended to illustrate one or more specific examples, and the scope of the present invention is not limited to these examples.
실험예 1: 정상 멜라닌세포와 흑색종세포에서의 비교 연구Experimental Example 1: Comparative study in normal melanocytes and melanoma cells
실험예 1-1: AC_774 준비 Experimental Example 1-1: Preparation of AC_774
*AC_774는 논문 'Identification of targets of the HIF-1 inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes.'(Bioconjug Chem 2016; 27:1911-1920. DOI: 10.1021/acs.bioconjchem.6b00305)에서 IDF-11774를 제조하는 방법에 따라 제조하였다. 수니티닙(Sunitinib)과 5-FU는 Sigma-Aldrich(St. Louis, MO, USA)에서 구입하였다. 소라페닙(Sorfenib) 및 라파티닙(lapatinib)은 Santa Cruz Biotechnology(Dalls, TX, USA)에서 구입하였다. 저장용액은 DMSO에서 10mM로 제조하고, -20℃에 저장하였다. *AC_774 is IDF-11774 in the paper 'Identification of targets of the HIF-1 inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes.' It was prepared according to the manufacturing method. Sunitinib and 5-FU were purchased from Sigma-Aldrich (St. Louis, MO, USA). Sorafenib (Sorfenib) and lapatinib (lapatinib) were purchased from Santa Cruz Biotechnology (Dalls, TX, USA). A stock solution was prepared at 10 mM in DMSO and stored at -20 °C.
실험예 1-2: 세포 종류 및 배양Experimental Example 1-2: Cell type and culture
정상 멜라닌 세포는 서로 다른 3명의 정상인에게 제공받은 피부조직으로부터 단일세포 현탁액을 만든 후, 소 뇌하수체 추출물 (bovine pituitary extract), 소인슐린 (bovinve insulin), 소태아혈청 (fetal bovine serum), 하이드로코르티존 (hydrocortisone), 소트랜스페린 (bovine transferrin), 염기성 섬유모세포 성장인자 (basic fibroblast growth factor), 헤파린 (heparin) 및 포볼 12-미리스테이트 13-아세테이트 (phorbol 12-myristate 13-acetate)를 포함하는 Medium 254(Invitrogen)에서 배양하였고, 7 내지 20번까지 계대배양하면서 실험에 사용하였다. 흑색종 세포주 Hs936T, MNT1, B16F10는 10% 소 태아 혈청(fetal bovine serum)을 포함하는 DMEM에서 배양하였다. Normal melanocytes were obtained by making a single cell suspension from skin tissues provided by three different normal people, and then using bovine pituitary extract, bovine insulin, fetal bovine serum, and hydrocortisone. Medium 254 containing hydrocortisone, bovine transferrin, basic fibroblast growth factor, heparin and phorbol 12-myristate 13-acetate (Invitrogen), and used in experiments while subcultured from 7 to 20 times. Melanoma cell lines Hs936T, MNT1, and B16F10 were cultured in DMEM containing 10% fetal bovine serum.
실험예 1-3: AC_774에 대한 세포 생존 실험 및 세포 독성 실험 Experimental Example 1-3: Cell survival test and cytotoxicity test for AC_774
세포 생존성은 MTT 환원 방법에 의하여 평가하였다. 세포는 MTT로 4시간동안 염색한 뒤, 침전된 포르마잔을 DMSO에서 용해시켰다. 그 후, 분광기를 이용하여 630nm에서 배경차분(background subtraction)하고, 570nm에서 광학밀도(opical density)를 측정하였다. AC_774의 효과는 DMSO를 처리한 경우의 세포생존율에 대한 AC_774를 처리한 경우의 세포 생존율의 비율로 계산하였다. DMSO 용매와 여러 농도의 AC_774는 2일동안 처리하여 세포 생존율을 측정하였고, 정상인의 멜라닌 세포에서 결과와 흑색종 세포주에서의 결과를 비교하였다. Cell viability was assessed by the MTT reduction method. After staining the cells with MTT for 4 hours, the precipitated formazan was dissolved in DMSO. Then, background subtraction was performed at 630 nm using a spectrometer, and optical density was measured at 570 nm. The effect of AC_774 was calculated as the ratio of cell viability when treated with AC_774 to cell viability when treated with DMSO. DMSO solvent and various concentrations of AC_774 were treated for 2 days to measure cell viability, and the results in normal melanocytes and melanoma cell lines were compared.
세포 독성은 전산탈수소효소(lactate dehydrogenase, LDH) 방출법으로 평가되었다. 세포독성검출키트(Roche, Penzberg, Germany)를 사용하여 배양 배지에서 LDH 활성을 측정하였다. 실험 배양액의 상층부에서 LDH 방출은 490nm에서 광학 밀도를 측정한 다음 620nm에서 광학 밀도를 빼서 측정하였다. 세포독성에 대한 화학 물질의 영향은 적절한 용매에 대한 각 화학물질의 LDH 방출 비율로 계산하였다. Cytotoxicity was evaluated by lactate dehydrogenase (LDH) release method. LDH activity was measured in the culture medium using a cytotoxicity detection kit (Roche, Penzberg, Germany). LDH release in the supernatant of the experimental culture was determined by measuring the optical density at 490 nm and then subtracting the optical density at 620 nm. The effect of chemicals on cytotoxicity was calculated as the ratio of LDH release of each chemical to an appropriate solvent.
실험예 2: 흑색종세포를 이식한 실험동물에서의 연구Experimental Example 2: Study in experimental animals transplanted with melanoma cells
실험예 2-1: 흑색종 유발농도 결정 연구Experimental Example 2-1: Determination of Melanoma Induced Concentration Study
한국 세포주 은행에서 구입한 흑색종 세포주 B16F10을 DMEM 배양액에서 배양하였다. 배양한 세포주를 200,000, 500,000개를 각각 100μL의 HBS 버퍼에 현탁하여 nude mouse 하복부(lower abdomen)의 피하에 각 농도에 따라 주사하였다. 실험 마우스는 각 농도별로 2마리씩 사용하였다. 1주 간격으로 종양 형성 유무를 확인하고, 크기를 측정하였다. 종양의 크기가 가로×세로×높이가 1cm×1cm×1cm가 될 때까지 관찰하였으며, 빠른 시간안에 원하는 크기에 도달하는 세포의 농도를 선택하여 실험하였다. The melanoma cell line B16F10 purchased from the Korean Cell Line Bank was cultured in DMEM medium. 200,000 and 500,000 of the cultured cell lines were respectively suspended in 100 μL of HBS buffer and injected subcutaneously into the lower abdomen of a nude mouse according to each concentration. Two experimental mice were used for each concentration. The presence or absence of tumor formation was checked at intervals of one week, and the size was measured. The size of the tumor was observed until the size of the tumor reached 1 cm × 1 cm × 1 cm in width × length × height, and the experiment was performed by selecting the concentration of cells that reached the desired size in a short time.
실험예 2-2: 실험동물에 흑색종 유발 및 AC_774 (IDF-11774) 투여Experimental Example 2-2: Induction of melanoma in experimental animals and administration of AC_774 (IDF-11774)
결정된 농도의 흑색종세포를 투여 농도당 4마리의 마우스 하복부에 피하 주사하였다. 종양이 1cm3 기준 크기에 도달하면 DMA 10%, Cremophor 5% 및 물 85%에 용해한 AC_774를 10mg/kg, 30mg/kg 및 60mg/kg 농도로 2주간 매일 경구투여하여 AC_774를 투여하지 않은 군에서의 결과와 비교하였다. A determined concentration of melanoma cells was subcutaneously injected into the lower abdomen of 4 mice per dose concentration. When the tumor reached the standard size of 1 cm 3 , AC_774 dissolved in 10% DMA, 5% Cremophor, and 85% water was orally administered at concentrations of 10 mg/kg, 30 mg/kg, and 60 mg/kg daily for 2 weeks. It was compared with the result of
실험예 2-3: AC_774의 흑색종에 대한 효과와 안전성 조사Experimental Example 2-3: Investigation of the effect and safety of AC_774 on melanoma
AC_774 경구투여 후 3일 간격으로 종양크기 및 형태 변화 등 임상적 결과를 비교하였다. 경구투여 2주 후 CO2로 안락사한 후, 각 군의 종양을 생검하여 종양의 크기와 무게를 측정하고, 조직 면역염색을 통한 세포수 괴사 및 염증세포 종류와 침윤 정도 등을 조직학적 변화를 비교하였다. Clinical results such as tumor size and morphological changes were compared at 3-day intervals after oral administration of AC_774. After euthanasia with CO 2 after 2 weeks of oral administration, tumors in each group were biopsied to measure tumor size and weight, and compare histological changes such as cell number, necrosis, inflammatory cell type and degree of infiltration through tissue immunostaining. did
실시예 1: AC_774 처리에 따른 정상 멜라닌 세포와 흑색종 세포의 HLF-1α 발현억제, 세포 생존율, 세포독성 비교Example 1: Comparison of HLF-1α expression inhibition, cell viability, and cytotoxicity in normal melanocytes and melanoma cells according to AC_774 treatment
3명의 정상인으로부터 배양한 멜라닌세포 (MC) 및 흑색종 세포주 B16F10 세포에 여러 농도의 AC_774를 2일간 처리하였을 때 세포 생존율, 세포독성 및 HLF-1α 발현억제 여부를 확인하였다.When melanocytes (MC) and melanoma cell line B16F10 cells cultured from three normal individuals were treated with AC_774 at various concentrations for 2 days, cell viability, cytotoxicity, and inhibition of HLF-1α expression were examined.
도 1에서 보이는 바와 같이, 세포 생존율과 세포독성을 비교한 결과, 정상 멜라닌 세포의 경우, 도 1에서 보이는 바와 같이, 6μM 까지는 70% 생존율을 보이는반면, 7μM 농도에서 생존율은 20% 정도로 낮아지는 것을 확인하였다. 세포독성도 6μM까지는 낮지만, 7μM부터는 현저히 증가하는 것을 확인하였으며, 멜라닌세포 독성을 나타내는 S100B 세포내외 농도에서도 7μM에서 유의한 증가를 확인하였다.As shown in Figure 1, as a result of comparing cell viability and cytotoxicity, in the case of normal melanocytes, as shown in Figure 1, while showing a 70% survival rate up to 6μM, the survival rate at a concentration of 7μM is as low as 20% Confirmed. Although the cytotoxicity is low up to 6 μM, it was confirmed that it significantly increased from 7 μM, and a significant increase was confirmed at 7 μM in the S100B intracellular and extracellular concentrations indicating melanocyte toxicity.
도 2에서 보이는 바와 같이, 흑색종 세포주 B16F10의 경우, 5μM 까지는 70% 생존율을 보이는 반면, 7μM부터 생존율의 유의한 감소가 있었다. 또한 저산소 환경하에서는 1.25μM까지는 생존율의 감소 폭이 적었지만 2.5μM부터 생존율의 유의한 감소가 있었다. 세포독성도 2.5μM부터 유의하게 증가하였으며, 저산소 환경하에서는 1.25μM부터 유의하게 증가함을 확인하였다.As shown in FIG. 2 , in the case of the melanoma cell line B16F10, the survival rate was 70% up to 5 μM, whereas the survival rate was significantly decreased from 7 μM. In addition, in a hypoxic environment, the decrease in survival rate was small until 1.25 μM, but there was a significant decrease in survival rate from 2.5 μM. Cytotoxicity was also significantly increased from 2.5 μM, and it was confirmed that it significantly increased from 1.25 μM in a hypoxic environment.
따라서, 저산소 환경하에서 AC_774는 저산소 환경이 아닌 경우에 비해 더 낮은 농도에서 흑색종에 대한 독성을 나타냄을 확인하였다.Therefore, it was confirmed that AC_774 exhibits toxicity against melanoma under a hypoxic environment at a lower concentration than in a non-hypoxic environment.
또한, HIF-1α의 발현억제 여부와 관련하여, 도 2에서 보이는 바와 같이, 정상 멜라닌 세포 대비 흑색종 세포주에서의 HIF-1α가 발현이 증가함을 확인하였다. 또한 CoCl2를 첨가하여 저산소 환경을 구축하여 HIF-1α가 발현한 정도를 확인한 결과, 흑색종세포는 정상 멜라닌 세포와 비교하여 HIF-1α가 발현이 유의하게 증가하여 저산소 상태에서 생존할 수 있는 체계를 가지고 있음을 확인할 수 있었다. 이에 AC_774를 투여하였고 그로인해 HIF-1α가 발현을 유의하게 감소시켜, AC_774가 HIF-1α발현을 억제함을 확인하였다.In addition, with regard to whether HIF-1α expression was suppressed, as shown in FIG. 2 , it was confirmed that HIF-1α expression increased in melanoma cell lines compared to normal melanocytes. In addition, as a result of confirming the degree of HIF-1α expression by establishing a hypoxic environment by adding CoCl 2 , the expression of HIF-1α significantly increased in melanoma cells compared to normal melanocytes, indicating that the system can survive in hypoxic conditions. I was able to confirm that I have Accordingly, AC_774 was administered, and as a result, the expression of HIF-1α was significantly reduced, confirming that AC_774 suppresses HIF-1α expression.
따라서 상기 결과를 종합하면, AC_774는 정상인 멜라닌세포에는 독성을 나타내지 않는 농도에서 B16F10 흑색종 세포주에서는 독성을 유발하였음을, 흑색종 세포주에서 HIF-1α의 발현을 억제하였음을 확인하였다. Therefore, taking the above results together, it was confirmed that AC_774 induced toxicity in the B16F10 melanoma cell line and inhibited the expression of HIF-1α in the melanoma cell line at a concentration that was not toxic to normal melanocytes.
실시예 2: 흑색종세포를 이식한 마우스에서 AC_774의 효과 확인Example 2: Confirmation of the effect of AC_774 in mice transplanted with melanoma cells
모든 실험은 생명윤리위원회(Institutional review board: IRB)가 승인한 실험에 따라 수행하였다(IRB 승인번호: 10-04217).All experiments were performed according to experiments approved by the Institutional review board (IRB) (IRB approval number: 10-04217).
실시예 2-1: Nude mouse에 흑색종을 유발하는 농도 결정Example 2-1: Determination of concentration inducing melanoma in nude mice
200,000개의 세포수가 피하주사에서도 3주후에는 3마리 중 2마리에서 각각 1.2 cm3와 1.7 cm3로 안락사 시켜야 할 정도의 크기인 1~1.5cm3를 초과하였다. AC_774는 2주간 경구투여 하여야 하므로 투여하지 않은 군을 감안할 때 흑색종 세포 투입부터 연구 종료까지 기간은 3주를 넘길 수 없다는 것을 확인하였다. 따라서 200,000개의 세포수를 피하주사 하여 흑색종을 유발하고 유발 1주 후부터 AC_774를 처리하여 효과를 관찰하였다.Even with subcutaneous injection, 200,000 cells were 1.2 cm 3 and 1.7 cm 3 respectively in 2 out of 3 mice after 3 weeks, exceeding the size of 1-1.5 cm 3 that should be euthanized. Since AC_774 must be administered orally for 2 weeks, it was confirmed that the period from the injection of melanoma cells to the end of the study could not exceed 3 weeks, considering the non-administered group. Therefore, melanoma was induced by subcutaneous injection of 200,000 cells, and the effect was observed by treating AC_774 from 1 week after induction.
실시예 2-2: AC_774의 흑색종 크기 감소 효과 확인Example 2-2: Confirmation of melanoma size reduction effect of AC_774
생검한 종양의 크기는 1/2LW2 (L: 종양 길이, W: 종양 폭) 공식에 넣어 계산하였다. 도 3에서 보이는 바와 같이, AC_774를 저농도(10mg/kg)로 처리한 군에서는 1마리가 일찍 사망하여 3마리만 연구를 완료하였고, 나머지 군은 4마리 모두 연구를 완료하였다. 도 4에서 보이는 바와 같이, 각 군당 종양크기가 차이가 나는 1마리씩을 제외하고 종양크기를 측정하였으며, 중농도(30mg/kg) 및 고농도(60mg/kg) 처리군에서 치료하지 않은 군 대비 현저히 감소하는 것을 확인하였다. The size of the biopsied tumor was calculated using the formula 1/2LW 2 (L: tumor length, W: tumor width). As shown in FIG. 3, in the group treated with AC_774 at a low concentration (10 mg/kg), 1 animal died early and only 3 animals completed the study, and all 4 animals in the other group completed the study. As shown in Figure 4, the tumor size was measured except for one animal with a difference in tumor size for each group, and the medium concentration (30mg / kg) and high concentration (60mg / kg) treatment group significantly decreased compared to the untreated group. confirmed that.
실시예 2-3: AC_774의 흑색종 세포사멸에 대한 효과와 안전성 확인Example 2-3: Confirmation of effect and safety of AC_774 on melanoma cell death
생검한 모든 종양을 파라핀 블록으로 만들어 H&E(hematyoxylin & erosin) 염색 외에 TUNEL 염색에 양성을 나타내는 세포인 사멸 세포의 비율을 계산하였다. 안전성에 대하여는 종양 인접한 조직에 TUNEL 양성세포 및 염증세포 침윤 등에 대하여 조사하였다. All biopsied tumors were made into paraffin blocks, and the percentage of apoptotic cells, which are cells showing positive for TUNEL staining in addition to H&E (hematyoxylin & erosin) staining, was calculated. For safety, TUNEL-positive cells and inflammatory cell infiltration were investigated in tissues adjacent to the tumor.
도 5 내지 도 7에서 보이는 바와 같이, AC_774를 투여하지 않은 군과 저농도 처리 군에서는 TUNEL 양성 세포 비율이 차이가 나지 않았으며, 중간농도를 처리한 군도 종양의 일부 부위에서 TUNEL 양성세포의 증가를 보였으나 차이가 현저하지 않았다. 그러나 도 8에서 보이는 바와 같이, 고농도 처리군에서는 TUNEL 양성 세포 비율이 증가하는 것을 확인하였다. 도 9에서 보이는 바와 같이, 세포 사멸 비율이 고농도 처리군에서 현저하였으며, 통계적 유의성은 나타나지 않았으나, 실험동물 수를 늘리면 유의성이 관찰될 것으로 생각된다. 또한, 도 11에서 보이는 바와 같이, 저산소 환경하에 cyclin-D의 발현이 증가하지만 AC_774 처리시 저산소 조건 유무에 관계없이 감소하고 저산소 상태에서 뚜렷하게 감소함을 확인하였으며, 활성-caspase3의 발현이 증가함을 확인하여 세포사멸을 증가시킴을 알 수 있었다. As shown in FIGS. 5 to 7, there was no difference in the ratio of TUNEL-positive cells in the group not administered with AC_774 and the group treated with low concentration, and the group treated with medium concentration also showed an increase in TUNEL-positive cells in some parts of the tumor. I didn't notice a difference. However, as shown in FIG. 8 , it was confirmed that the ratio of TUNEL-positive cells increased in the high concentration treatment group. As shown in Figure 9, the cell death rate was remarkable in the high concentration treatment group, and statistical significance was not shown, but it is thought that significance will be observed when the number of experimental animals is increased. In addition, as shown in FIG. 11, although the expression of cyclin-D increases under hypoxic conditions, it was confirmed that it decreased regardless of the presence or absence of hypoxic conditions during AC_774 treatment, and it was clearly decreased under hypoxic conditions, and the expression of active-caspase3 increased. It was confirmed that it increased apoptosis.
도 5 내지 도 9 및 도 11의 결과를 종합해보면, 종양에 인접한 조직에는 AC_774 농도에 관계없이 TUNEL 양성세포와 염증세포의 침윤이 관찰되지 않았으며, AC_774는 농도에 비례하여 흑색종의 크기를 감소시킨다는 것을 확인하였다. Summarizing the results of FIGS. 5 to 9 and 11, TUNEL-positive cells and inflammatory cell infiltration were not observed in tissues adjacent to the tumor regardless of the concentration of AC_774, and AC_774 reduced the size of melanoma in proportion to the concentration confirmed that it does.
실시예 2-4: AC_774의 흑색종 내 CD8 양성 세포독성 T 세포 침윤 정도 확인Example 2-4: Determination of CD8-positive cytotoxic T cell infiltration in melanoma of AC_774
생검한 모든 종양을 파라핀 블록을 만들어 CD8 항체로 조직면역형광검사를 시행하였고, 전체 종양 대비 CD8 양성을 나타내는 T세포의 염색강도를 측정하여 비교하였다. 도 10A에서 보이는 바와 같이, AC_774를 투여하지 않은 군에서는 종양의 크기가 너무 커서 참고막대 길이가 다른 군보다 작을 정도로 크기를 줄였으나 종양의 일부만 현미경하에서 관찰이 가능하였다. 또한, 30mg/kg 투여군도 60mg/kg 투여군 대비 종양 크기가 크다는 것을 확인하였다. All biopsied tumors were made into paraffin blocks, and tissue immunofluorescence was performed with CD8 antibody, and the staining intensity of CD8-positive T cells compared to all tumors was measured and compared. As shown in FIG. 10A, the size of the tumor in the group not administered with AC_774 was so large that the length of the reference bar was reduced to a smaller extent than that of the other groups, but only a portion of the tumor could be observed under a microscope. In addition, it was confirmed that the tumor size of the 30mg/kg administration group was larger than that of the 60mg/kg administration group.
도 10에서 보이는 바와 같이, CD8 양성 세포독성 T세포는 종양 내에서 주로 관찰되었고 형광염색의 강도는 그래프에서와 같이 AC_774 투여군에서 투여하지 않은 군 대비 유의하게 증가하였으며 중간농도 투여군보다 고농도 투여군에서 높게 나타나므로 농도에 의존적인 성향을 나타내었다. 또한, 고농도 투여군의 경우 T세포가 군집한 종양부위에는 세포가 소실되어 생긴 것 같은 공간들도 관찰되었다.As shown in FIG. 10, CD8-positive cytotoxic T cells were mainly observed in the tumor, and the intensity of fluorescence staining was significantly increased in the AC_774-administered group compared to the non-administered group as shown in the graph, and was higher in the high-concentration-administered group than in the medium-concentration-administered group. Therefore, it showed a concentration-dependent tendency. In addition, in the case of the high concentration administration group, spaces that appeared to be caused by cell loss were observed in the tumor area where T cells were clustered.
실시예 3: AC_774의 hypoxia 노출 유무에 따른 흑색종 세포에 작용 확인Example 3: Confirmation of action of AC_774 on melanoma cells with and without hypoxia exposure
저산소 환경에 적응하기 위한 세포나 조직의 일차적인 반응은 산소에 민감한 전사활성인자인 HIF-1 (hypoxia-inducible factor-1)에 의하여 구성요소의 하나인 HIF-1α는 산소에 의해 조절된다. 또한, 흑색종 세포의 경우 다른 암세포들과 유사하게 저산소 환경에서 HIF-1α의 발현이 증가하는데 저산소에 노출된 세포에 HIF-1α의 축적을 억제하면 저산소 환경에서 과발현하는 PDL1(programmed cell death ligand-1)이라는 면역억제분자의 전사가 억제되어 세포독성 T세포에 의한 면역반응으로부터의 도피가 감소함이 밝혀졌다. 이들 결과는 본 연구의 AC_774 투여군에서 종양크기감소, 종양세포사멸 및 종양 내 세포독성 T세포수 등의 결과와 유사한 부분이 있다. 따라서 B16F10 흑색종 세포에 산화스트레스를 유발하고 AC_774의 HIF-1α의 발현에 대한 효과를 확인하였다. 또한, 도 1에서 확인한 바와 같이, AC_774가 정상 멜라닌세포보다 B16F10 흑색종 세포에서 세포독성이 증가하였으므로 흑색종 세포와 정상 멜라닌 세포에서 HIF-1α 발현 정도도 비교하였다. The primary response of cells or tissues to adapt to a hypoxic environment is oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1), one of the components of which is regulated by oxygen. In addition, in the case of melanoma cells, the expression of HIF-1α increases in a hypoxic environment, similar to other cancer cells. When the accumulation of HIF-1α is suppressed in cells exposed to hypoxia, PDL1 (programmed cell death ligand- It was found that the transcription of the immunosuppressive molecule called 1) was suppressed, thereby reducing the escape from the immune response by cytotoxic T cells. These results are similar to the results of tumor size reduction, tumor cell death, and intratumoral cytotoxic T cell count in the AC_774 administration group in this study. Therefore, oxidative stress was induced in B16F10 melanoma cells, and the effect of AC_774 on HIF-1α expression was confirmed. In addition, as confirmed in FIG. 1, since AC_774 showed increased cytotoxicity in B16F10 melanoma cells than in normal melanocytes, the degree of HIF-1α expression in melanoma cells and normal melanocytes was also compared.
도 1A에서 보이는 바와 같이, Hs936T, MNT1 및 B16F10 흑색종 세포들에서 정상 멜라닌세포 대비 HIF-1α 발현이 높다는 것을 확인하였으며, 이는 흑색종을 포함한 암세포에서 HIF-1α가 높은 발현을 보인다는 보고와 일치하였다. As shown in Figure 1A, it was confirmed that HIF-1α expression was higher in Hs936T, MNT1 and B16F10 melanoma cells compared to normal melanocytes, which is consistent with the report that HIF-1α is expressed high in cancer cells including melanoma. did
또한, 도 11에서 보이는 바와 같이, B16F10 흑색종 세포에 CoCl2 (Cobalt chloride) 처리하여 산화스트레스를 유발하였다. AC_774를 처리하지 않은 경우, B16F10 흑색종세포는 HIF-1α 발현이 유의하게 증가하여 저산소 환경에서 적응할 수 있음을 확인하였다. 그러나 AC_774를 투여하면 HIF-1α 발현 증가가 AC_774 농도에 의존적으로 억제되는 것을 확인하였다. In addition, as shown in FIG. 11 , oxidative stress was induced by CoCl 2 (Cobalt chloride) treatment to B16F10 melanoma cells. When AC_774 was not treated, B16F10 melanoma cells showed a significant increase in HIF-1α expression, confirming that they could adapt to a hypoxic environment. However, when AC_774 was administered, it was confirmed that the increase in HIF-1α expression was suppressed dependently on the concentration of AC_774.
실시예 4: AC_774 처리에 의한 흑색종 세포주의 전이 억제 효과 확인Example 4: Confirmation of metastasis inhibitory effect of melanoma cell lines by AC_774 treatment
암 전이 여부를 확인하기 위해서는 EMT(epithelial-mesenchymal transition)가 전이의 주요 기전 중 하나이다. cytokeratin, E cadherin 및 occludin과 같은 상피 표지자는 하향 조절되는 반면, N-cadherin, vimentin 및 fibronectin과 같은 중간엽 표지자는 EMT에서 상향 조절된다.In order to determine whether cancer has metastasized, epithelial-mesenchymal transition (EMT) is one of the main mechanisms of metastasis. Epithelial markers such as cytokeratin, E cadherin and occludin are downregulated, whereas mesenchymal markers such as N-cadherin, vimentin and fibronectin are upregulated in EMT.
AC_774에 의해 흑색종 세포주의 전이 억제 효과가 있는지 확인하기 위해서 EMT에 관여하는 인자인 E-cadherin, N-cadherin 및 SNAIL 단백질의 발현변화를 배양세포 및 동물종양에서 조사하였다.In order to confirm whether AC_774 has an inhibitory effect on melanoma cell line metastasis, changes in the expression of E-cadherin, N-cadherin, and SNAIL proteins, which are factors involved in EMT, were investigated in cultured cells and animal tumors.
도 12에서 보이는 바와 같이, CoCl2 처리하에 N-cadherin 및 SNAIL의 발현이 증가되고, E-cadherin 발현은 감소하여 저산소증에 의한 EMT 자극을 확인하였다. AC_774 처리하에 E-cadherin발현 수준이 다시 회복하고, N-cadherin 및 SNAIL의 발현이 감소함을 확인하였다. As shown in FIG. 12 , under CoCl 2 treatment, the expression of N-cadherin and SNAIL increased, and the expression of E-cadherin decreased, confirming EMT stimulation by hypoxia. It was confirmed that E-cadherin expression level recovered again under AC_774 treatment, and N-cadherin and SNAIL expression decreased.
따라서, 저산소증은 N-cadherin 및 SNAIL을 상향조절하고, E-cadherin는 하향조절하여 흑색종에서 EMT를 촉진함을 확인할 수 있었다. 이에 AC_774는 N-cadherin 및 SNAIL을 하향조절시키고, E-cadherin은 상향조절하여 흑색종의 성장 및 전이를 억제할 수 있음을 확인하였다,Therefore, it was confirmed that hypoxia promoted EMT in melanoma by upregulating N-cadherin and SNAIL, and downregulating E-cadherin. Accordingly, it was confirmed that AC_774 can down-regulate N-cadherin and SNAIL, and up-regulate E-cadherin to suppress melanoma growth and metastasis.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다. The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.
본 발명의 범위는 후술하는 청구범위에 의하여 나타내어지며, 청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention.
Claims (8)
- 하기 화학식 1로 표기되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating melanoma, comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.[화학식 1][Formula 1]
- 제 1항에 있어서, According to claim 1,상기 흑색종은 선단 흑색점성 흑색종, 결절성 흑색종, 표재 확장성 흑색종, 악성 흑색점 흑색종인 것인, The melanoma is acromegaly melanoma, nodular melanoma, superficial disseminated melanoma, and malignant lentigo melanoma,흑색종 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating melanoma.
- 하기 화학식 1로 표기되는 화합물을 포함하는 흑색종 예방 또는 개선용 건강기능식품 조성물.A health functional food composition for preventing or improving melanoma comprising a compound represented by Formula 1 below.[화학식 1][Formula 1]
- 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는 조성물을 흑색종 질환 의심 개체에 투여하는 단계를 포함하는 흑색종 예방 또는 치료 방법.A method for preventing or treating melanoma, comprising administering a composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject suspected of melanoma disease.
- 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 흑색종 전이 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating melanoma metastasis comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient.[화학식 1] [Formula 1]
- 제 5항에 있어서,According to claim 5,상기 조성물은 N-cadherin, vimentin, fibronectin 및 SNAIL로 이루어진 군에서 선택된 하나 이상의 단백질 발현을 하향조절하는 것을 특징으로 하는 조성물.The composition is characterized in that the down-regulation of the expression of one or more proteins selected from the group consisting of N-cadherin, vimentin, fibronectin and SNAIL.
- 제 5항에 있어서, According to claim 5,상기 조성물은 cytokeratin, E cadherin 및 occludin로 이루어진 군에서 선택된 하나 이상의 단백질 발현을 상항조절하는 것을 특징으로 하는 조성물.The composition is characterized in that the up-regulation of the expression of one or more proteins selected from the group consisting of cytokeratin, E cadherin and occludin.
- 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, N-카드헤린(N-cadherin) 발현이 증가된 흑색종 전이 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating metastasis of melanoma with increased expression of N-cadherin, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.[화학식 1] [Formula 1]
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| KR20180002361A (en) * | 2016-06-29 | 2018-01-08 | 동국대학교 산학협력단 | Probe for detecting HSP70 and manufacturing method thereof |
| KR20190052255A (en) * | 2017-11-08 | 2019-05-16 | 한국생명공학연구원 | Composition for preventing or treating cancer comprising IDF-11774 and autolysosome formation inhibitor |
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| KR101930904B1 (en) | 2017-05-08 | 2018-12-19 | 염창환 | Composition for preventing or treating melanoma comprising hyaluronidase |
| KR102274238B1 (en) * | 2020-01-23 | 2021-07-09 | 동국대학교 산학협력단 | Disubstituted adamantyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition and kit for inhibiting the growth of cancer containing the same as an active ingredient |
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| KR20190052255A (en) * | 2017-11-08 | 2019-05-16 | 한국생명공학연구원 | Composition for preventing or treating cancer comprising IDF-11774 and autolysosome formation inhibitor |
| US20200352936A1 (en) * | 2019-05-09 | 2020-11-12 | Hampton University | Methods of treating keloids |
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| KARAMOOZIAN NAJMEH; DEHESTANI MARYAM; BEHJATMANESH-ARDAKANI REZA: "Investigation of the interaction of hypoxia-inducible factor 1-alpha inhibitor, IDF-11774, with heat shock protein, HSP70, using quantum chemistry calculations", STRUCTURAL CHEMISTRY, vol. 31, no. 4, 19 February 2020 (2020-02-19), New York, pages 1419 - 1428, XP037181691, ISSN: 1040-0400, DOI: 10.1007/s11224-020-01501-3 * |
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