WO2023075062A1 - Composition pour la prévention ou le traitement du mélanome, comprenant ac_774 - Google Patents

Composition pour la prévention ou le traitement du mélanome, comprenant ac_774 Download PDF

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Publication number
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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melanoma
formula
compound represented
preventing
composition
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PCT/KR2022/008067
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English (en)
Korean (ko)
Inventor
이애영
정경아
김난형
이경
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동국대학교 산학협력단
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Publication of WO2023075062A1 publication Critical patent/WO2023075062A1/fr

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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
    • 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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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne une composition pour la prévention ou le traitement du mélanome, comprenant un composé représenté par la formule chimique 1. Dans la présente invention, les effets de l'induction de la toxicité, la réduction de la taille du mélanome, l'augmentation de l'infiltration de lymphocytes T cytotoxiques CD8+ dans le mélanome et l'inhibition de la métastase du mélanome ont été identifiés dans des lignées cellulaires de mélanome, et ainsi la présente invention peut être utilisée dans la prévention, le soulagement et le traitement d'un mélanome ou d'une métastase de mélanome.
PCT/KR2022/008067 2021-10-29 2022-06-08 Composition pour la prévention ou le traitement du mélanome, comprenant ac_774 WO2023075062A1 (fr)

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Application Number Priority Date Filing Date Title
KR10-2021-0146450 2021-10-29
KR20210146450 2021-10-29
KR10-2022-0068873 2022-06-07
KR1020220068873A KR102459443B1 (ko) 2021-10-29 2022-06-07 Ac_774를 포함하는 흑색종 예방 또는 치료용 조성물

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180002361A (ko) * 2016-06-29 2018-01-08 동국대학교 산학협력단 Hsp70 탐지용 프로브 및 이의 제조방법
KR20190052255A (ko) * 2017-11-08 2019-05-16 한국생명공학연구원 Idf-11774 및 자가용해소체 형성 저해제를 포함하는 암의 예방 또는 치료용 조성물
US20200352936A1 (en) * 2019-05-09 2020-11-12 Hampton University Methods of treating keloids

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KR101380466B1 (ko) * 2011-09-27 2014-04-02 한국생명공학연구원 ＨＩＦ―１α 활성을 저해하는 신규 화합물 및 그 제조방법
KR101930904B1 (ko) 2017-05-08 2018-12-19 염창환 히알루로니다제를 포함하는 흑색종 예방 또는 치료용 조성물
KR102274238B1 (ko) * 2020-01-23 2021-07-09 동국대학교 산학협력단 이치환 아다만틸 유도체, 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 포함하는 암 성장 억제용 약학적 조성물

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Publication number Priority date Publication date Assignee Title
KR20180002361A (ko) * 2016-06-29 2018-01-08 동국대학교 산학협력단 Hsp70 탐지용 프로브 및 이의 제조방법
KR20190052255A (ko) * 2017-11-08 2019-05-16 한국생명공학연구원 Idf-11774 및 자가용해소체 형성 저해제를 포함하는 암의 예방 또는 치료용 조성물
US20200352936A1 (en) * 2019-05-09 2020-11-12 Hampton University Methods of treating keloids

Non-Patent Citations (2)

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Title
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 *
KIM MIN-HEE, LEE TAE HYEONG, LEE JIN SOO, LIM DONG-JUN, LEE PETER CHANG-WHAN: "Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro", PHARMACEUTICALS, vol. 13, no. 9, pages 208, XP093062246, DOI: 10.3390/ph13090208 *

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