WO2021241862A1 - Composition pharmaceutique pour la prévention ou le traitement du cancer, comprenant un inhibiteur d'inositol polyphosphate multikinase utilisé comme principe actif - Google Patents

Composition pharmaceutique pour la prévention ou le traitement du cancer, comprenant un inhibiteur d'inositol polyphosphate multikinase utilisé comme principe actif Download PDF

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WO2021241862A1
WO2021241862A1 PCT/KR2021/003295 KR2021003295W WO2021241862A1 WO 2021241862 A1 WO2021241862 A1 WO 2021241862A1 KR 2021003295 W KR2021003295 W KR 2021003295W WO 2021241862 A1 WO2021241862 A1 WO 2021241862A1
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cancer
pharmaceutical composition
tumor
vilazodone
preventing
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PCT/KR2021/003295
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Korean (ko)
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김세윤
이보아
박승주
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한국과학기술원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P35/02—Antineoplastic agents specific for leukemia

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  • the present invention was made under project number NRF-2018R1A2B2005913 supported by the Ministry of Science and ICT A study on the function of metabolic stress signal regulation by polyphosphate multikinase”, organized by the Korea Advanced Institute of Science and Technology, and the research period is from March 1, 2019 to February 29, 2020.
  • the present invention has been made under project number NRF-2018R1A5A1024261 under the support of the Ministry of Science and ICT.
  • the host institution is the Korea Advanced Institute of Science and Technology, and the research period is from 2019.03.01 to 2020.02.29.
  • the present invention relates to a pharmaceutical composition for preventing or treating cancer comprising an inositol polyphosphate multikinase inhibitor as an active ingredient.
  • Colorectal cancer is a malignant tumor that occurs in the appendix, colon, and rectum, and occurs in the mucous membrane, the innermost surface of the large intestine. Colorectal cancer is the second most common cancer in Korea after gastric cancer. In recent years, the incidence of colorectal cancer has increased sharply with the westernization of diet. Its rate of increase continues to increase.
  • colorectal cancer can be divided into surgical resection, chemotherapy, and radiation therapy.
  • Polyps which are the previous stages of colorectal cancer, or early colon/rectal cancer limited to polyps, can be treated with polypectomy.
  • fluorescent anticancer drugs such as irinotecan, oxaliplatin, capecitabine, and TAS-102 and epithelial cell growth cetuximab, Panitu, as a targeted anticancer agent that targets epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), or vascular endothelial growth factor receptor (VEGF-R)
  • EGFR epidermal growth factor receptor
  • VEGF vascular endothelial growth factor
  • VEGF-R vascular endothelial growth factor receptor
  • the present inventors made intensive research efforts to develop compounds for inhibiting cancer cell growth and killing cancer cells. As a result, in the case of a composition comprising an Inositol Polyphosphate Multikinase (IPMK) inhibitor as an active ingredient, it was found that it is effective in cancer treatment, thereby completing the present invention.
  • IPMK Inositol Polyphosphate Multikinase
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising an IPMK inhibitor as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising an inositol polyphosphate multikinase inhibitor as an active ingredient.
  • Inositol polyphosphate is an inositol metabolite synthesized by sequential phosphorylation of inositol 1,4,5-trisphosphate (IP3) by a series of inositol kinases and biosynthesis, and is bound to the inositol ring structure It is called IP4, IP5, or IP6 depending on the number of phosphate groups.
  • IP7 and IP8 can be synthesized, and this type of inositol polyphosphate is specifically called inositol pyrophosphate.
  • IPMK Inositol polyphosphate multikinase
  • the IPMK inhibitor may refer to a substance that inhibits the activity of IPMK itself or inhibits the activity of an upper-level factor that increases the activity of IPMK.
  • the IPMK inhibitor has the effect of inhibiting the activity of IPMK, regulating the activation of the Akt signaling pathway, and inhibiting the growth of cancer cells through reduction of Akt 473 phosphorylation. Therefore, IPMK inhibitors may exhibit anticancer effects against various carcinomas.
  • the inositol polyphosphate multikinase inhibitor is vilazodone.
  • Villazodone (trade name: Viibryd) is a drug used as an antidepressant developed by Merck in Germany, and the US approved the use of vilazodone as an antidepressant in 2011.
  • vilazodone is 5-(4-[4-(5-cyano-1H-indole-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide (5-(4 -(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide).
  • the inositol polyphosphate multikinase inhibitor is vilazodone, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
  • the cancer is a solid cancer.
  • solid cancer has characteristics distinguishing it from blood cancer, and includes bladder, breast, intestine, kidney, lung, liver, brain, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin. It is a cancer consisting of a mass caused by abnormal cell growth in various solid organs such as
  • the solid cancer is brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal/sinus cancer , nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, Pancreatic cancer, small intestine cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer,
  • the cancer is a hematologic cancer.
  • hematologic cancer refers to cancer occurring in components constituting blood, and refers to malignant tumors occurring in blood, hematopoietic organs, lymph nodes, lymphatic organs, and the like.
  • the hematologic cancer is acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute monocytic leukemia, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. is selected from, but not limited thereto.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the composition as an active ingredient.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil; it is not going to be
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
  • a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, a talct, a talct, a talct, a stevia, glycerin, glycerin, glycerin,
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, for example, intrathecal administration, intravenous administration, subcutaneous administration, intradermal administration, intramuscular administration, intraperitoneal administration, intrasternal administration, intratumoral administration, intranasal administration , intracerebral administration, intracranial administration, intrapulmonary administration, rectal administration, etc., but is not limited thereto.
  • a suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and response sensitivity of the patient, An ordinarily skilled physician can readily determine and prescribe an effective dosage (a pharmaceutically effective amount) for the desired treatment or prophylaxis.
  • the daily dose of the pharmaceutical composition of the present invention is 0.0001-100 mg/kg.
  • the term “pharmaceutically effective amount” refers to an amount sufficient to prevent or treat the above-mentioned diseases.
  • prevention refers to the prevention or protective treatment of a disease or disease state.
  • treatment refers to reduction, suppression, sedation or eradication of a disease state.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. or may be prepared by incorporation into a multi-dose container.
  • the dosage form can be prepared in various ways such as oral medicine, injection, etc., in the form of a solution, suspension or emulsion in oil or aqueous medium, or in the form of an extract, powder, suppository, powder, granule, tablet or capsule, dispersant or stable Additional topics may be included.
  • the pharmaceutical composition comprising vilazodone of the present invention has the effect of inhibiting the activity of IPMK and increasing the expression of proteins involved in the autophagy mechanism of cells.
  • the pharmaceutical composition of the present invention has the effect of inhibiting the growth of cancer cells and the effect of inhibiting the growth of tumors in vivo. Therefore, the pharmaceutical composition of the present invention has an anticancer effect on cancer, more specifically colon cancer.
  • the present invention provides a method for preventing or treating cancer comprising administering to a subject a pharmaceutical composition comprising the above-described inositol polyphosphate multikinase inhibitor of the present invention as an active ingredient provides
  • administer refers to directly administering a therapeutically or prophylactically effective amount of a composition of the present invention to a subject (individual) suffering from, or likely to suffer from, the subject disease. It means that the same amount is formed in the body of
  • the "therapeutically effective amount” of the composition means an amount of the composition sufficient to provide a therapeutic or prophylactic effect to a subject to which the composition is to be administered, and includes a “prophylactically effective amount”.
  • the term "subject (subject)” is a mammal including humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, monkeys, chimpanzees, baboons and rhesus monkeys. . Most specifically, the subject of the present invention is a human.
  • the method for preventing or treating cancer of the present invention includes administering the pharmaceutical composition according to an aspect of the present invention, the description thereof is omitted to avoid excessive redundancy of the present specification for overlapping content. .
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising an inositol polyphosphate multikinase inhibitor as an active ingredient.
  • composition of the present invention can be used as an anticancer agent by inhibiting the growth of cancer cells and exhibiting the efficacy of killing cancer cells.
  • Figure 1a shows the results of analyzing the inhibitory effect of inositol kinase activity of vilazodone through IP kinase assay.
  • Figure 1b shows the results of analyzing the metabolites of IPMK after treating NIH3T3-L1 fibroblasts with DMSO, vilazodone, and quercetin through HPLC.
  • Figure 1c shows the result of analyzing the phosphorylation level of Akt after treatment with DMSO drug and vilazodone for HCT116 cells through Western blot.
  • Figure 2a shows the results of analyzing the cell viability after treating the colon cancer cell line HCT116 with DMSO and vilazodone, respectively.
  • Figure 2b shows the results of analyzing the cell viability after treating the colon cancer cell line HT29 with DMSO and vilazodone, respectively.
  • Figure 2c shows the results of analyzing the cell viability after treating the colon cancer cell line SW480 with DMSO and vilazodone, respectively.
  • FIG. 3 shows the results of analysis of proteins related to autophagy of cells after treatment with DMSO and vilazodone for three representative colorectal cancer cell lines (HCT116, HT29, SW480) through Western blot.
  • % used to indicate the concentration of a specific substance is (weight/weight) % for solid/solid, (weight/volume) % for solid/liquid, and Liquid/liquid is (volume/volume) %.
  • HCT116 cells human colon cancer cells, p53 wild-type
  • HT29 cells human colon cancer cells, p53 mutant
  • SW480 cells human colon cancer cells, p53 mutant
  • HCT116 cells were cultured in McCoy's 5a medium (Sigma Aldrich, Missouri, USA) supplemented with 2 mM glutamine, 1% penicillin-streptomycin and 10% fetal bovine serum (FBS) at 37 ° C. and 5% CO 2 conditions.
  • HT29 and SW480 cells were cultured in RPMI medium (Sigma Aldrich, Missouri, USA) supplemented with 2 mM glutamine, 1% penicillin-streptomycin, and 10% fetal bovine serum (FBS) at 37 ° C. and 5% CO 2 conditions. .
  • Example 2-1 IPMK inhibitory effect of vilazodone confirmed by performing IP kinase assay
  • the IPMK inhibitory effect of vilazodone was measured using the ADP-Glo Kinase kit (Promega, Wisconsin, USA).
  • kinase assay buffer 50 mM HEPES [pH 7.4], 10 mM MgCl2, 50 mM KCl), 50 ng recombinant IPMK, 10 ⁇ M ATP, and 100 ⁇ M vilazodone or quercetin (Sigma Aldrich, Missouri, USA) was added to the experiment. The reaction was quenched with ADP-Glo reagent at room temperature for 40 min. After that, kinase detection substrate was added and the reaction was incubated for an additional 30 minutes. Luminescence was detected by plate reading.
  • Example 2-2 IPMK inhibitory effect of vilazodone confirmed by HPLC
  • NIH3T3-L1 fibroblasts (2 ⁇ 10 5 cells) were inoculated in DMEM 60 mm medium supplemented with 10% calf serum. Cells were labeled with 60 ⁇ Ci [ 3 H]-myo-inositol for 3 days.
  • Villazodone and quercetin were dissolved in DMSO to a concentration of 0.1%, and 10 ⁇ M of vilazodone or quercetin dissolved in DMSO was treated for the experiment.
  • Soluble inositol metabolites were extracted with perchloric acid buffer, and the remaining insoluble inositol metabolites were extracted using 0.1 M NaOH and 0.1% Triton X-100. 3H-labeled IP was analyzed by high performance liquid chromatography (HPLC), and each fraction was measured using a liquid scintillation counter.
  • Example 2-3 IPMK inhibitory effect of vilazodone confirmed by immunoblotting
  • HCT116 cells were seeded in a 6-well plate at a density of 4 ⁇ 10 4 cells/well and treated with 10 ⁇ M of vilazodone one day later. After 4 h of vilazodone treatment, cells were washed with NP-40 buffer (50 mM Tris-HCl [pH 7.5], 150 mM NaCl, 1% NP-40, 1 mM EDTA [pH 8.0], 50 mM NaF, 10 mM Na-Pi). lysate, and a cocktail of protein inhibitors [Roche, Switzerland]). The cell lysate was loaded on a 4 to 12% Bis-Tris SDS-PAGE gel, and transferred to a nitrocellulose membrane.
  • Phospho-S473 Akt, Total Akt (Cell Signaling Technology, Massachusetts, USA), and ⁇ -tubulin (Sigma Aldrich, Missouri, USA) antibodies were diluted 1:1,000 and used.
  • the secondary antibody was diluted 1:2,000 and used. Proteins were detected using a chemiluminescent immunoblot detection system (Bio-Rad, California USA).
  • HCT116, HT29, SW480 cells were seeded in 96-well plates at a density of 10 4 cells/well, incubated at 37 °C for 24 hours, and then at various concentrations (0, 1.25, 2.5, 5, 10, 20 ⁇ M) of Villa It was treated with crude pigs (Selleckchem, Texas, USA). After treatment with vilazodone Plates were incubated at 5% CO 2 , 37° C. for 24, 48, 72 hours. Thereafter, 100 ⁇ L of an assay reagent was added to each well of the cells, and luminescence was measured using a VICTOR X Multilabel Reader (PerkinElmer, Massachusetts, USA), and is shown in FIG. 2 .
  • TBST a mixture of tris-buffered saline (TBS) and Tween 20
  • Cell signaling horseradish peroxidase-conjugated secondary antibody
  • ECL enhanced chemiluminescence
  • vilazodone significantly decreased the phosphorylation level of ULK1 and significantly increased the induction of LC3I to LC3II in a concentration-dependent manner ( FIG. 3 ). These results indicate that vilazodone has the effect of significantly increasing the expression of proteins involved in the autophagy mechanism.
  • Example 5 Assay for colony growth of vilazodone-treated cells (cell colony forming assay)
  • the cancer cell colony growth rate was examined when vilazodone was added to the wells culturing HT29 cells.
  • HT29 cells were seeded in a 12-well plate at a density of 10 5 cells/well, and after incubation at 37° C. for 24 hours, the cells were treated with 0, 5, 10, 20 ⁇ M vilazodone. After treatment with vilazodone Plates were incubated at 5% CO 2 , 37° C. for 48 hours. After that, 500 ⁇ L of crystal violet was added to each well, and the cells were stained at room temperature for 10 minutes to analyze the proliferation of the cells.

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement du cancer, comprenant un inhibiteur d'inositol polyphosphate multikinase utilisé comme principe actif. La composition selon la présente invention révèle les effets d'inhibition de la croissance de cellules cancéreuses et de mort des cellules cancéreuses et peut donc être utilisée comme agent anticancéreux.
PCT/KR2021/003295 2020-05-26 2021-03-17 Composition pharmaceutique pour la prévention ou le traitement du cancer, comprenant un inhibiteur d'inositol polyphosphate multikinase utilisé comme principe actif WO2021241862A1 (fr)

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Cited By (1)

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CN116125070A (zh) * 2022-08-22 2023-05-16 苏州大学 Trim21作为进展期结肠癌的诊断标志物及其应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116125070A (zh) * 2022-08-22 2023-05-16 苏州大学 Trim21作为进展期结肠癌的诊断标志物及其应用
CN116125070B (zh) * 2022-08-22 2023-09-29 苏州大学 Trim21作为进展期结肠癌的诊断标志物及其应用

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