WO2021167175A1 - Composition pharmaceutique utilisée dans la prévention ou le traitement du cancer comprenant un inhibiteur de signalisation mtor comme principe actif - Google Patents

Composition pharmaceutique utilisée dans la prévention ou le traitement du cancer comprenant un inhibiteur de signalisation mtor comme principe actif Download PDF

Info

Publication number
WO2021167175A1
WO2021167175A1 PCT/KR2020/007922 KR2020007922W WO2021167175A1 WO 2021167175 A1 WO2021167175 A1 WO 2021167175A1 KR 2020007922 W KR2020007922 W KR 2020007922W WO 2021167175 A1 WO2021167175 A1 WO 2021167175A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
lomitapide
tumor
pharmaceutical composition
cells
Prior art date
Application number
PCT/KR2020/007922
Other languages
English (en)
Korean (ko)
Inventor
김세윤
이보아
박승주
Original Assignee
한국과학기술원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국과학기술원 filed Critical 한국과학기술원
Priority to CN202180015980.0A priority Critical patent/CN115135322A/zh
Priority to EP21757494.6A priority patent/EP4108242A4/fr
Priority to US17/800,627 priority patent/US20230346762A1/en
Priority to JP2022550038A priority patent/JP2023514717A/ja
Priority to PCT/KR2021/002105 priority patent/WO2021167389A1/fr
Priority to KR1020210022880A priority patent/KR20210107548A/ko
Publication of WO2021167175A1 publication Critical patent/WO2021167175A1/fr
Priority to KR1020220035035A priority patent/KR20220042087A/ko
Priority to KR1020230020096A priority patent/KR20230028737A/ko

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating cancer comprising an mTOR signaling 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, and its incidence has increased sharply with the westernization of eating habits. Its rate of increase continues to increase.
  • colorectal cancer can be divided into surgical resection, chemotherapy, and radiation therapy.
  • Polyps which are the pre-stage of colorectal cancer, or early colon/rectal cancer limited to polyps, can be treated with polypectomy.
  • fluorescent anticancer drugs such as irinotecan, oxaliplatin, capecitabine, TAS-102, and epithelial cell growth cetuximab, Panitu, 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
  • mTOR (mechanistic target of rapamycin) protein is a serine/threonine kinase and is a key signaling factor that regulates cell growth, cell cycle, protein synthesis and glucose metabolism.
  • PI3K, Akt emtors and higher-level factors
  • Activation of emtor signals in cancer is caused by mutations in the emtor gene itself, high-level oncogenes (PI3K, Akt) that enhance the activity of emtor, and mutations in tumor suppressor factors (eg PTEN, TSC1/2).
  • inhibition of emtor-associated signaling may induce cell autophagy along with protein synthesis inhibition, lipid synthesis inhibition, and cell growth inhibition, leading to cell death. Therefore, there is a need for the development of an emtor-related signaling inhibitor for the inhibition of cancer cell growth and cancer cell death.
  • the present inventors made intensive research efforts to develop compounds for inhibiting cancer cell growth and killing cancer cells. As a result, the present invention was completed by identifying that the composition comprising an mTOR signaling inhibitor as an active ingredient is effective in treating cancer.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising an mTOR signaling inhibitor as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising an mTOR signaling inhibitor as an active ingredient.
  • the emtor signal transduction inhibitor refers to a substance that inhibits the activity of emtor itself or inhibits the activity of an upper-level factor that increases the activity of emtor.
  • the target whose activity is inhibited by the emtor signaling inhibitor may include, but is not limited to, emtor, PI3K, Akt, S6K, and S6.
  • the emtor signaling inhibitor is lomitapide.
  • Lomitapide (trade names Jaxtapid (US), Lojuxta (EU)) is a rare disease treatment developed by Aegerion Pharmaceuticals and is used as a cholesterol lowering agent in the treatment of familial hypercholesterolemia.
  • US Jaxtapid
  • EU Lojuxta
  • FDA U.S. Food and Drug Administration
  • the IUPAC name of lomitapide is N- (2,2,2-trifluoroethyl)-9-[4-[4-[[[4'-(trifluoromethyl)[1,1'-biphenyl] ] 2-yl] carbonyl] amino] -1-piperidinyl] butyl] -9 H - fluoren-9-carboxylic a copy polyimide
  • the lomitapide is represented by the following formula (I).
  • the emtor signaling inhibitor is lomitapide, 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 myeloid 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 active ingredient, lomitapide, a pharmaceutically acceptable salt thereof, or an optical isomer thereof.
  • 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, and the like. it's 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 mode, 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 may 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 lomitapide of the present invention has the effect of inhibiting the emtor signaling process and increasing the expression of proteins involved in the autophagy mechanism of cells.
  • autophagy is a destructive process that naturally decomposes unnecessary or non-functional cellular components in the control process of cells.
  • the autophagy-related genes include ULK1, mTOR, ATG family, DDIT4, and the like.
  • ULK1 is a gene encoding a protein kinase required for the initiation of autophagy, and ULK1 activity is suppressed under conditions of high mTOR protein activity. When mTOR activity is inhibited, the increase in ULK1 activity directs it to initiate autophagy-related signaling.
  • mTOR As a protein kinase, mTOR is a key factor in the inhibition of autophagy as well as the regulation of cell growth and activity. mTOR directly phosphorylates ULK1 and various autophagy proteins to mediate the inhibition of autophagy. Conversely, autophagy is actively promoted under conditions in which mTOR activity is inhibited.
  • ATG family genes are Autophagy-Related Genes composed of more than 30 key genes involved in the initiation and progression of autophagy. These genes are necessary for the whole process of autophagy, including the initiation of autophagy, the formation of the autophagic membrane, the recognition of the substrate to be degraded, and the fusion reaction between the autophagy membrane and lysosome.
  • DDIT4 also known as REDD1
  • DDIT4 is a protein that inhibits mTOR through the TSC protein. Therefore, an increase in DDIT4 is a gene that increases the activity of autophagy by inducing inhibition of mTOR.
  • 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 is cancer, more specifically blood cancer, skin cancer, colorectal cancer, brain cancer, ovarian cancer, bladder cancer, breast cancer, uterine cancer, duodenal cancer, fibrosarcoma, kidney cancer, liver cancer, lung cancer, pancreatic cancer, It has anticancer effects against prostate cancer, stomach cancer, bone tumor, endometrial cancer, etc.
  • the present invention provides a method for preventing or preventing cancer comprising administering to a subject a pharmaceutical composition comprising the above-described mTOR signaling inhibitor of the present invention as an active ingredient. provide a treatment method.
  • 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 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 mTOR signaling 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 2 shows the results of analyzing the shape of the cells after treating the normal human intestinal epithelial cells and colon cancer cell line HCT116 with DMSO control drug and lomitapide, respectively.
  • Figure 3 shows the results of analyzing the cell viability after treating the normal human intestinal epithelial cells and colon cancer cell line HCT116 with DMSO control drug and lomitapide, respectively.
  • Figure 5a shows the results of analyzing the cell viability after lomitapide treatment for brain cancer cell lines.
  • Figure 5b shows the results of analyzing the viability of cells after treatment with lomitapide targeting breast cancer cell lines.
  • Figure 5c shows the results of analyzing the viability of the cells after lomitapide treatment on a blood cancer cell line.
  • Figure 5d shows the results of analyzing the cell viability after treatment with lomitapide targeting colon cancer cell lines.
  • Figure 5e shows the results of analyzing the viability of cells after treatment with lomitapide targeting lung cancer cell lines.
  • Figure 5f shows the results of analyzing the viability of the ovarian cancer cell line after treatment with lomitapide.
  • 5g shows the results of analyzing the cell viability of gastric cancer cell lines after treatment with lomitapide.
  • Figure 5h shows the results of analyzing the cell viability after treatment with lomitapide in bladder cancer, bone cancer, duodenal cancer, endometrial cancer, fibrosarcoma, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, and skin cancer cell lines.
  • FIG. 6 shows the results of analyzing proteins related to emtor signaling in cells after treatment with a DMSO control drug and lomitapide for colon cancer cells HCT116 through Western blot.
  • Figure 7a shows the results of analysis of proteins related to emtor signaling and autophagy in the colon cancer cells SW480 after treatment with DMSO control drug and lomitapide through Western blot.
  • Figure 7b shows the results of analysis of proteins related to emtor signaling and autophagy in cells after treatment with DMSO control drug and lomitapide for colorectal cancer cells HT29 through western blot.
  • Figure 7c shows the results of analyzing the proteins related to emtor signaling and autophagy in the cells after treatment with DMSO control drug and lomitapide for breast cancer cells MDA-MB-231 through Western blot.
  • Figure 7d shows the results of analyzing the proteins related to emtor signaling and autophagy in the cells after treatment with DMSO control drug and lomitapide for breast cancer cells MDA-MB-468 through Western blot.
  • Figure 9 shows the results of analysis of apoptosis by autophagy after treating the human colorectal cancer cell line HCT116 with DMSO control drug, lomitapide, and 3-methylamine (3-MA), respectively, through Western blot.
  • FIG. 10 shows the results of analysis of apoptosis by autophagy after the human colon cancer cell line HCT116 was treated with a DMSO control drug, lomitapide, and 3-methylamine (3-MA), respectively, through a microscope.
  • FIG. 11 shows the results of analyzing the significant gene-mechanism relationship using RNA-seq analysis after treating the human colon cancer cell line HCT116 with DMSO control drug and lomitapide, respectively.
  • FIG. 13 shows the results of measuring the degree of cancer cell colony proliferation after treating colon cancer cells HCT116 with DMSO control drug and lomitapide.
  • Figure 14a shows the results of comparing and analyzing the change in tumor size with the control group after treatment with lomitapide (50 mg/Kg) of colorectal cancer cells HCT116 xenografted into mice.
  • Figure 14b shows the results of analyzing the change in tumor size after treatment with lomitapide (25, 50 mg/Kg) of colorectal cancer cells HCT116 xenografted into mice.
  • Figure 14c shows the results of analyzing the change in tumor size after treatment with lomitapide (10 mg/Kg) of colon cancer cells xenografted to mice HCT116.
  • % 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) %.
  • NCM460 cells human colon normal cells
  • 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
  • MDA-MB-231 cells human breast cancer cells
  • MDA-MB-468 cells human breast cancer cells
  • HCT116 cells were grown in McCoy's 5a medium (Sigma Aldrich, Missouri, USA) supplemented with 2 mM glutamine, 1% penicillin-streptomycin and 10% fetal bovine serum (FBS). 37 °C, 5% CO 2 Incubated under conditions.
  • HT29, SW480 cells were cultured in RPMI medium supplemented with 2 mM glutamine, 1% penicillin-streptomycin and 10% fetal bovine serum (FBS) (Sigma Aldrich, Missouri, USA). 37 °C, 5% CO 2 Incubated under conditions.
  • MDA-MB-231 and MDA-MB-468 cells were cultured in DMEM medium (Sigma Aldrich, Missouri, USA) supplemented with 2 mM glutamine, 1% penicillin-streptomycin and 10% fetal bovine serum (FBS) at 37°C, 5 % CO 2 Incubated under conditions.
  • DMEM medium Sigma Aldrich, Missouri, USA
  • FBS fetal bovine serum
  • Example 2 Viability assay of cells treated with lomitapide
  • Example 2-1 Viability analysis of lomitapide-treated colon cancer cells
  • NCM460, 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, 2, 5, 10 ⁇ M). It was treated with tapide (Sigma Aldrich, Missouri, USA). After lomitapide treatment Plates were incubated at 5% CO 2 , 37° C. for 24 hours. Thereafter, 100 ⁇ L of assay reagent (CellTiter-Glo® Reagent) was added to each well and luminescence was measured using a VICTOR X Multilabel Reader (PerkinElmer, Massachusetts, USA). %) was calculated. The results are shown in FIGS. 2 to 4 .
  • Example 2-2 Viability analysis of lomitapide-treated cancer cells
  • cells were treated with lomitapide , incubated for 72 hours at 37 °C in 5% CO 2 or 10% CO 2 conditions, equilibrated to room temperature for 1 hour, and CellTiterGlo reagent (Promega) was added. After 1 hour, the luminescence was measured, and the cell viability (%) was calculated therefrom. 120 types of cells were purchased from ATCC (American Type Culture Collection, Virginia, USA) and used.
  • lomitapide had anticancer effects at very low concentrations in various carcinomas and cancer cell lines, and the types were blood cancer, skin cancer, colorectal cancer, brain cancer, ovarian cancer, bladder cancer, breast cancer, uterine cancer, duodenal cancer, fibrosarcoma, kidney cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, gastric cancer, bone tumor, endometrial cancer, and the like.
  • Example 3 Cell signaling assay of lomitapide-treated cells
  • the supernatant obtained above was separated by loading on a 10% SDS-PAGE gel, and the separated protein was blotted on a PVDF membrane. Then, the antibody was added to the blot as follows (Table 2), and incubated at 4° C. for 12 hours.
  • TBST a mixture of tris-buffered saline (TBS) and Tween 20), and at 37 °C, 1 with horseradish peroxidase-conjugated secondary antibody (Cell signaling). for time After incubation and washing, enhanced chemiluminescence (ECL; Amersham) was detected.
  • Lomitapide-treated at various concentrations (0, 5, 10 ⁇ M) for analysis of changes in cell signaling involved in cell autophagy HCT116 cells were analyzed by Western blot.
  • Western blotting the supernatant obtained in Example 3 was loaded on a 10% SDS-PAGE gel to separate, and the separated protein was blotted on a PVDF membrane. Then, anti-p-AMPK, anti-LC3, and anti-p-ULK1 antibodies (Cell Signaling Technology, Massachusetts, USA) were added to the blot, and incubated at 4° C. for 12 hours.
  • TBST a mixture of tris-buffered saline (TBS) and Tween 20), and at 37 °C, 1 with horseradish peroxidase-conjugated secondary antibody (Cell signaling). for time After incubation and washing, enhanced chemiluminescence (ECL; Amersham) was detected.
  • Lomitapide-treated at 5 ⁇ M for analysis of changes in cell signaling involved in cell autophagy HCT116 cells and HCT116 cells treated with 1-mM 3-MA and 5 ⁇ M of lomitapide were analyzed by Western blot.
  • the Western blotting procedure is the same as the Western blotting procedure described above except that anti-LC3 was used as the antibody.
  • HCT116 cells were inoculated into a 96-well plate at a density of 10 4 cells/well, and incubated at 37°C for 24 hours, 5 ⁇ M of lomitapide, 3-MA 1 mM or 5 It was treated with ⁇ M lomitapide and 1-mM 3-MA. after processing Plates were incubated at 5% CO 2 , 37° C. for 24 hours. Thereafter, 100 ⁇ L of an assay reagent (CellTiter-Glo® Reagent) was added to each well and the results were observed under a microscope.
  • an assay reagent CellTiter-Glo® Reagent
  • HCT116 cells treated with lomitapide and 3-MA significantly reduced the induction of LC3I to LC3II ( FIG. 9 ).
  • cell death was inhibited in the case of HCT116 cells treated with lomitapide and 3-MA through cell viability analysis (FIG. 10).
  • lomitapide of the present invention inhibits AMPK and mTOR signaling processes, thereby increasing the expression of cellular autophagy mechanism proteins.
  • Example 5 Analysis of significant gene expression and mechanism of lomitapide-treated cells (RNA-seq assay)
  • GSEA Gene set enrichment analysis
  • Pathway enrichment analysis was performed to analyze genes that are significantly expressed through RNA-seq experiments and related mechanisms to confirm the relationship between the drug mechanism of lomitapide and genes. was carried out through
  • GSEA is an analysis method for extracting a significant gene-set in which expression values of two classes show a statistically significant difference from among various gene-sets constructed based on biological characteristics.
  • genes with specific functions among all genes used in RNA-seq experiments using a gene annotation database (KEGG pathway, Gene Ontology, etc.) with various biological information about genes were identified.
  • KEGG pathway Gene Ontology, etc.
  • Various gene-sets were discovered by grouping, and significant genes were determined by referring to the difference in expression values between two classes within each gene-set, and statistically significant gene-sets were finally detected based on this.
  • cancer-related mechanisms related to the Emtor mechanism including autophagy were detected, and in addition, immune, aging, and diabetes-related mechanisms were detected ( FIG. 11 , Table 3).
  • DEG analysis is an analysis that selects a candidate group for a significant gene (Differentially Expressed Genes) with a difference in expression between the control group and the control group by measuring and statistically processing the expression value of the gene.
  • Example 6 Cell colony forming assay of lomitapide-treated cells
  • HCT116 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 ⁇ M lomitapide. After lomitapide treatment Plates were incubated at 5% CO 2 , 37° C. for 48 hours. Thereafter, 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.
  • Example 7 Analysis of the anticancer effect of lomitapide confirmed through animal experiments
  • HCT116 cells (4x10 6 ) were implanted by subcutaneous injection into male BALB/c nude mice aged 8-12 weeks. After the mean tumor volume reached 50 mm 3 , mice were randomly assigned to two different groups (5 mice/group). The mouse body weight and tumor diameter were measured once every two days. Tumor volume was evaluated according to the general formula 0.5x(width) 2 x(Length) using a caliper, and Student's T test was used to determine P-values. For lomitapide treatment, 1, 2, 3, 7, 8, 9, 13, 14, 15, and 16 days after the start of the experiment, 50 mg/kg of lomitapide was administered to the mouse. Injected into the abdominal cavity. As a control, DMSO was injected intraperitoneally into mice ( FIG. 14A ).
  • mice were injected intraperitoneally into mice ( FIG. 14b ).

Abstract

La présente invention concerne une composition pharmaceutique permettant de prévenir ou de traiter le cancer comprenant un inhibiteur de signalisation mTOR comme principe actif. La composition de la présente invention présente l'efficacité d'inhiber la croissance des cellules cancéreuses et de tuer les cellules cancéreuses, et peut donc être utilisée comme agent anticancéreux.
PCT/KR2020/007922 2020-02-21 2020-06-18 Composition pharmaceutique utilisée dans la prévention ou le traitement du cancer comprenant un inhibiteur de signalisation mtor comme principe actif WO2021167175A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CN202180015980.0A CN115135322A (zh) 2020-02-21 2021-02-19 包含哺乳动物雷帕霉素靶蛋白信号传导抑制剂作为有效成分的用于预防或治疗癌症的药物组合物
EP21757494.6A EP4108242A4 (fr) 2020-02-21 2021-02-19 Composition pharmaceutique permettant de prévenir ou de traiter le cancer contenant un inhibiteur de signalisation mtor comme principe actif
US17/800,627 US20230346762A1 (en) 2020-02-21 2021-02-19 Pharmaceutical composition for preventing or treating cancer, containing mtor-signaling inhibitor as active ingredient
JP2022550038A JP2023514717A (ja) 2020-02-21 2021-02-19 エムトール信号伝達抑制剤を有効成分として含む癌の予防又は治療用薬剤学的組成物
PCT/KR2021/002105 WO2021167389A1 (fr) 2020-02-21 2021-02-19 Composition pharmaceutique permettant de prévenir ou de traiter le cancer contenant un inhibiteur de signalisation mtor comme principe actif
KR1020210022880A KR20210107548A (ko) 2020-02-21 2021-02-19 엠토르 신호전달 억제제를 유효성분으로 포함하는 암의 예방 또는 치료용 약제학적 조성물
KR1020220035035A KR20220042087A (ko) 2020-02-21 2022-03-21 엠토르 신호전달 억제제를 유효성분으로 포함하는 암의 예방 또는 치료용 약제학적 조성물
KR1020230020096A KR20230028737A (ko) 2020-02-21 2023-02-15 엠토르 신호전달 억제제를 유효성분으로 포함하는 암의 예방 또는 치료용 약제학적 조성물

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20200021549 2020-02-21
KR10-2020-0021549 2020-02-21

Publications (1)

Publication Number Publication Date
WO2021167175A1 true WO2021167175A1 (fr) 2021-08-26

Family

ID=77391998

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/007922 WO2021167175A1 (fr) 2020-02-21 2020-06-18 Composition pharmaceutique utilisée dans la prévention ou le traitement du cancer comprenant un inhibiteur de signalisation mtor comme principe actif

Country Status (2)

Country Link
KR (1) KR20210107548A (fr)
WO (1) WO2021167175A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114209698A (zh) * 2021-12-31 2022-03-22 中国药科大学 洛美他派在制备治疗溃疡性结肠炎的药物中的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070254883A1 (en) * 2006-01-25 2007-11-01 Crew Andrew P Unsaturated mTOR inhibitors
KR20130013264A (ko) * 2011-07-27 2013-02-06 한국과학기술원 이미다조피리딘 유도체, 이를 포함하는 ＰＩ3Ｋ 및/또는 ｍＴＯＲ 저해제용 약학 조성물 및 ＰＩ3Ｋ 및/또는 ｍＴＯＲ과 연관된 질환 치료용 약학 조성물
US20140171456A1 (en) * 2011-07-26 2014-06-19 Merck Sharp & Dohme Corp. FUSED TRICYCLIC COMPOUNDS AS mTOR INHIBITORS
US20180125812A1 (en) * 2016-11-04 2018-05-10 Emory University Dehydroacetic Acid (DHAA) and Derivative for Uses in Treating Cancer
WO2018204416A1 (fr) * 2017-05-02 2018-11-08 Revolution Medicines, Inc. Analogues de la rapamycine utilisés en tant qu'inhibiteurs de mtor
KR20190139637A (ko) * 2018-06-08 2019-12-18 재단법인 의약바이오컨버젼스연구단 신규 mTOR 저해제를 포함하는 암 예방 또는 치료용 조성물

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070254883A1 (en) * 2006-01-25 2007-11-01 Crew Andrew P Unsaturated mTOR inhibitors
US20140171456A1 (en) * 2011-07-26 2014-06-19 Merck Sharp & Dohme Corp. FUSED TRICYCLIC COMPOUNDS AS mTOR INHIBITORS
KR20130013264A (ko) * 2011-07-27 2013-02-06 한국과학기술원 이미다조피리딘 유도체, 이를 포함하는 ＰＩ3Ｋ 및/또는 ｍＴＯＲ 저해제용 약학 조성물 및 ＰＩ3Ｋ 및/또는 ｍＴＯＲ과 연관된 질환 치료용 약학 조성물
US20180125812A1 (en) * 2016-11-04 2018-05-10 Emory University Dehydroacetic Acid (DHAA) and Derivative for Uses in Treating Cancer
WO2018204416A1 (fr) * 2017-05-02 2018-11-08 Revolution Medicines, Inc. Analogues de la rapamycine utilisés en tant qu'inhibiteurs de mtor
KR20190139637A (ko) * 2018-06-08 2019-12-18 재단법인 의약바이오컨버젼스연구단 신규 mTOR 저해제를 포함하는 암 예방 또는 치료용 조성물

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114209698A (zh) * 2021-12-31 2022-03-22 中国药科大学 洛美他派在制备治疗溃疡性结肠炎的药物中的应用

Also Published As

Publication number Publication date
KR20210107548A (ko) 2021-09-01

Similar Documents

Publication Publication Date Title
WO2021167389A1 (fr) Composition pharmaceutique permettant de prévenir ou de traiter le cancer contenant un inhibiteur de signalisation mtor comme principe actif
WO2008088088A1 (fr) Composition destinée au traitement du cancer pancréatique
US10821127B2 (en) Composition for inhibiting myeloid-derived suppressor cells comprising decitabine or its pharmaceutically acceptable salt as active ingredient
Han et al. Ginkgo biloba exocarp extracts inhibits angiogenesis and its effects on Wnt/β-catenin-VEGF signaling pathway in Lewis lung cancer
WO2015160213A1 (fr) Composition pour la prévention ou le traitement de maladies hépatiques graisseuses
WO2020085642A1 (fr) Composition pharmaceutique permettant la prévention ou le traitement du cancer, contenant du n-1h-benzimidazol-2-yl-3-(1h-pyrrole-1-yl) benzamide en tant que principe actif
WO2019083172A1 (fr) Composition pharmaceutique permettant la prévention ou le traitement du cancer, contenant comme principes actifs de la streptonigrine et de la rapamycine
WO2021167175A1 (fr) Composition pharmaceutique utilisée dans la prévention ou le traitement du cancer comprenant un inhibiteur de signalisation mtor comme principe actif
WO2022055285A1 (fr) Composition pharmaceutique destinée à tuer des cellules progénitrices cancéreuses
WO2018155921A1 (fr) Composition pharmaceutique destinée à prévenir et à traiter le cancer du pancréas, contenant du gossypol et de la phénformine à titre de principes actifs
WO2016072692A2 (fr) Composition pour prévenir ou traiter la mucosite, comprenant du necrox en tant que principe actif
WO2022245089A1 (fr) Composition pour le traitement de la covid-19 comprenant de l'acide taurodésoxycholique ou un sel pharmaceutiquement acceptable correspondant en tant que principe actif
WO2021241862A1 (fr) Composition pharmaceutique pour la prévention ou le traitement du cancer, comprenant un inhibiteur d'inositol polyphosphate multikinase utilisé comme principe actif
WO2018147612A1 (fr) Composition destinée à inhiber la métastase cancéreuse et à traiter le cancer
US5994328A (en) Hypoestoxides, derivatives and agonists thereof for use as anticancer agents
WO2017217796A1 (fr) Inhibiteur de rhoa et son utilisation
WO2014051359A1 (fr) Composition pharmaceutique comprenant de la néférine comme ingrédient actif de prévention contre un hépatome ou de traitement de ce dernier
WO2015111971A1 (fr) Composition pharmaceutique contenant un ligand gpr119 comme principe actif pour prévenir ou traiter une stéatose hépatique non alcoolique
WO2022005228A1 (fr) Composition pharmaceutique pour la prévention ou le traitement du cancer comprenant un inhibiteur de la 3-cétoacyl-coa thiolase et un inhibiteur des transporteurs de la carnitine acylcarnitine
WO2024058551A1 (fr) Composition pharmaceutique pour le traitement du cancer du foie comprenant du cannabidiol et un agent anticancéreux en tant que principes actifs et son utilisation
WO2023059040A1 (fr) Composition pharmaceutique comprenant un inhibiteur de cdk et un activateur d'id2 pour la prévention ou le traitement du cancer de la vessie
WO2018169283A1 (fr) Nouvelle utilisation du rigosertib pour le traitement d'une maladie causée par le virus de l'hépatite c
WO2020054981A1 (fr) Composition pour le traitement ou la prévention du cancer comprenant le 2-(3-[2-(1-cyclohexen-1-yl)éthyl]-6,7-diméthoxy-4-oxo-3,4-dihydro-2-quinazolinylsulfanyl)-n-(4-éthylphényl)butanamide utilisé comme principe actif
WO2023244026A1 (fr) Composition pharmaceutique comprenant un inhibiteur de foxm1 et un inhibiteur de point de contrôle immunitaire, et destinée à la prévention ou au traitement du cancer
CN110051847A (zh) 醋酸棉酚和自噬抑制剂的联合用药物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20920370

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20920370

Country of ref document: EP

Kind code of ref document: A1