WO2021025018A1 - Composition pharmaceutique pour le traitement et/ou la prophylaxie du cancer colorectal - Google Patents

Composition pharmaceutique pour le traitement et/ou la prophylaxie du cancer colorectal Download PDF

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WO2021025018A1
WO2021025018A1 PCT/JP2020/029832 JP2020029832W WO2021025018A1 WO 2021025018 A1 WO2021025018 A1 WO 2021025018A1 JP 2020029832 W JP2020029832 W JP 2020029832W WO 2021025018 A1 WO2021025018 A1 WO 2021025018A1
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cancer
nfkbiz
item
composition according
legnes
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PCT/JP2020/029832
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English (en)
Japanese (ja)
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誠司 小川
伸之 垣内
大石　潤
良作 稲垣
上田　豊
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国立大学法人京都大学
大日本住友製薬株式会社
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Publication of WO2021025018A1 publication Critical patent/WO2021025018A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to a pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor and / or a Regnes 1 enhancer. It is also intended to provide a screening method for selecting substances or factors that treat and / or prevent cancer.
  • Non-Patent Document 1 Chronic inflammation is a condition in which the activities of inflammatory substances, cells, etc. do not converge even though the tissue abnormalities have been resolved, making it more susceptible to various diseases and becoming a serious risk factor for carcinogenesis.
  • Non-Patent Document 2 Chronic inflammation is characterized by an excessive immune response, repeated tissue damage and tissue repair. Among the cells that make up tissue repair, the presence of cells with gene mutations related to carcinogenesis has been reported, and repeated tissue damage and tissue repair with aging further increases the risk of carcinogenesis. It is known to increase (Non-Patent Document 2).
  • IBD Inflammatory bowel disease
  • Ulcerative colitis is a major inflammatory bowel disease, and is characterized by a pathological condition in which chronic inflammation occurs in a wide range of intestinal tracts, resulting in damage to the intestinal mucosa and intractable ulcers.
  • enterative colitis enterative colitis-related carcinogenesis in ulcerative colitis; epithelial associated carcinoma (CAC)
  • CAC epithelial associated carcinoma
  • the present disclosure relates to a pharmaceutical composition for treating and / or preventing cancer, which comprises an NFKBIZ inhibitor and / or a Regnes 1 enhancer. It is also intended to provide a screening method for selecting substances that treat and / or prevent cancer.
  • the present inventors have found that the NFKBIZ inhibitor and / or the Regnes 1 enhancer show a special growth inhibitory effect on cancer.
  • the present inventors have identified that the large intestine mucosal cells of patients with ulcerative colitis have a specific gene mutation, and the gene mutation is "characteristic of inflammatory bowel disease.” It was found that it is deeply involved in "repeated tissue damage and tissue regeneration related to pathological conditions" and "development and proliferation of inflammatory carcinogenesis”. Among these gene mutations, the NFKBIZ deficient mutation suppresses the production of inflammatory cytokines in tissues in a mouse enteritis model, alleviates enteritis associated with tissue destruction and regeneration, and causes carcinogenesis and cancer cells in the inflammatory mucosa. It was found to suppress proliferation.
  • NFKBIZ is an epoch-making drug discovery for the treatment and / or prevention of colorectal cancer. I found it to be a target.
  • the present disclosure includes:
  • a pharmaceutical composition for treating and / or preventing cancer which comprises an NFKBIZ inhibitor.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mela
  • Item 7 The pharmaceutical composition according to Item 6, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 12 The pharmaceutical composition according to any one of Items 1 to 11, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence. ..
  • Item 16 The pharmaceutical composition according to Item 14, wherein the inhibitor is an anti-NFKBIZ antibody.
  • Item 17 The pharmaceutical composition according to Item 14, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a pharmaceutical composition for treating and / or preventing cancer which comprises a Legnes 1 enhancer.
  • Item 20 The pharmaceutical composition according to Item 19, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 21 The pharmaceutical composition according to Item 20, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 22 The pharmaceutical composition according to Item 21, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • Item 25 The pharmaceutical composition according to Item 24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 28 The pharmaceutical composition according to any one of Items 19 to 27, wherein the enhancer inhibits a legnes monodegrading enzyme.
  • Item 29 The pharmaceutical composition according to Item 28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 30 The pharmaceutical composition according to Item 29, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 31 The pharmaceutical composition according to any one of Items 19 to 30, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 32 The pharmaceutical composition according to Item 31, wherein the enhancer is a nucleic acid.
  • Item 33 The pharmaceutical composition according to Item 26, wherein the enhancer is an antibody.
  • Item 34 The pharmaceutical composition according to Item 26, wherein the enhancer is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a pharmaceutical composition for treating and / or preventing cancer which comprises an E3 ligase inhibitor.
  • Item 37 The pharmaceutical composition according to Item 36, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 38 The pharmaceutical composition according to Item 37, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 39 The pharmaceutical composition according to Item 38, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • Item 41 The pharmaceutical composition according to Item 40, wherein the cancer is colorectal cancer.
  • Item 42 The pharmaceutical composition according to Item 41, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 43 The pharmaceutical composition according to any one of Items 36 to 42, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  • Item 44 The pharmaceutical composition according to any one of Items 36 to 43, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 45 The pharmaceutical composition according to Item 44, wherein the inhibitor is a nucleic acid.
  • Item 46 The pharmaceutical composition according to Item 44, wherein the inhibitor is an anti-E3 ligase antibody.
  • Item 47 The pharmaceutical composition according to Item 44, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • NFKBIZ inhibitor for use in the treatment and / or prevention of cancer.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • NFKBIZ inhibitor for use according to any one of Items A1 to A13, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant lymphoma, plasma
  • Item A25 Legnes 1 for use according to item A24, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. Enhancer.
  • legnes 1 enhancer for use according to item A28, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • legnes 1 enhancer for use according to item A29, wherein the enhancer has an E3 ligase inhibitory activity.
  • the legnace 1 enhancer for use according to any one of items A19 to A31, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • legnes 1 enhancer for use according to item A31, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • E3 ligase inhibitor for use in the treatment and / or prevention of cancer.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer.
  • Esophageal cancer thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Item A36 to include at least one selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma.
  • E3 ligase inhibitor for use according to any one of A39.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B17, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, stomach cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B34, which is benzoic acid (GS143).
  • a method for treating and / or preventing cancer in a subject which comprises a step of administering an effective amount of an E3 ligase inhibitor to the subject.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B47, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C17, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C34, which is benzoic acid (GS143).
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasmacytoma, multiple myeloma, myelodystrophy syndrome, brain tumor, head and neck cancer.
  • Esophageal cancer thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, gastrointestinal tract Interstitial tumor, chorionic villus epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, testicle tumor, testis Item C36 to include at least one selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and soft sarcoma. Use according to any one of C39.
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C47, which is benzoic acid (GS143).
  • a subject in which the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ is increased is (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ. 49.
  • Item 51 The composition according to item 49 or 50, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 52 The composition according to Item 51, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 53 The composition according to Item 52, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, malignant lymphoma
  • Item 56 The composition according to Item 55, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 58 The composition according to any one of Items 49 to 57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  • Item 59 The composition according to any one of Items 49 to 58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • Item 61 The composition according to any one of Items 49 to 60, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  • Item 62 The composition according to any one of Items 49 to 61, wherein the inhibitor has an E3 ligase inhibitory activity.
  • Item 65 The composition according to Item 63, wherein the inhibitor is an anti-NFKBIZ antibody.
  • Item 66 The composition according to Item 63, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • NFKBIZ inhibitor for use in the treatment and / or prevention of cancer, wherein the NFKBIZ inhibitor is used in subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ.
  • An NFKBIZ inhibitor characterized in that it is administered.
  • a subject in which the expression of NFKBIZ is increased and / or the activity of NFKBIZ is increased is (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ.
  • NFKBIZ inhibitor for use according to item A49 characterized in that it is determined in a step comprising determining that is elevated.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • NFKBIZ inhibitor for use according to any one of items A49 to A57, wherein the inhibitor reduces the expression of NFKBIZ and / or suppresses the function of NFKBIZ.
  • NFKBIZ inhibitor for use according to any one of items A49 to A58, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • NFKBIZ inhibitor for use according to any one of Items A49 to A62, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a method for treating and / or preventing cancer in a subject which comprises the step of administering to the subject an effective amount of NFKBIZ inhibitor, in which the subject has increased expression of NFKBIZ and / or.
  • a method of being a subject with elevated NFKBIZ activity comprises the step of administering to the subject an effective amount of NFKBIZ inhibitor, in which the subject has increased expression of NFKBIZ and / or.
  • (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ.
  • B49 The method of item B49, further comprising a step of determining that is rising.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B66, which is benzoic acid (GS143).
  • a subject in which the expression of NFKBIZ is increased and / or the activity of NFKBIZ is increased is (1) A step of measuring the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C66, which is benzoic acid (GS143).
  • Item 68 A method for predicting the efficacy of an NFKBIZ inhibitor on a subject, which comprises measuring the gene expression of NFKBIZ and / or the activity of NFKBIZ in the cancer cells of the subject.
  • Item 6 The method according to Item 68, which is determined in a step including a step of determining that the activity of NFKBIZ is increased.
  • Item 70 The method according to item 68 or 69, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 72 The method according to Item 71, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • Item 75 The method of item 74, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 7 The method according to any one of Items 68 to 75, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  • Item 78 The method according to any one of Items 68 to 77, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • Item 79 The method according to any one of Items 68 to 78, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  • Item 80 The method according to any one of Items 68 to 79, wherein the inhibitor inhibits a transcription factor composed of a complex containing NFKBIZ from interacting with a specific DNA sequence.
  • Item 8 The method according to any one of Items 68 to 79, wherein the inhibitor has an E3 ligase inhibitory activity.
  • Item 8 The method according to any one of Items 68 to 81, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 8 The method according to Item 82, wherein the inhibitor is a nucleic acid.
  • Item 85 The method according to Item 82, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • [Item 87] A method for screening an NFKBIZ inhibitor. (1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing an inhibitor candidate to act on cancer cells. (2) The step of measuring the gene expression and / or activity of NFKBIZ after allowing the inhibitor candidate to act on the cancer cells, and when the results of (3) and (2) are smaller than the results of (1). In addition, a step of determining the inhibitor candidate as an NFKBIZ inhibitor, Including methods.
  • [Item 88] A method for screening a therapeutic and / or preventive agent for cancer.
  • (1) A step of measuring gene expression and / or activity of NFKBIZ without allowing a therapeutic and / or prophylactic agent candidate to act on cancer cells.
  • (2) The steps of measuring the gene expression and / or activity of NFKBIZ after allowing the therapeutic and / or prophylactic agent candidate to act on the cancer cells, and the results of (3) and (2) are the results of (1).
  • a method for screening a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ (1) A step of measuring the gene expression and / or activity of NFKBIZ without allowing a test substance to act on cancer cells. (2) The step of measuring the gene expression and / or activity of NFKBIZ after allowing the test substance to act on the cancer cells, and when the results of (3) and (2) are smaller than the results of (1). In addition, a step of determining that the test substance is a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ. Including methods.
  • Item 90 The method according to any one of Items 87 to 89, wherein the cancer is a cancer associated with chronic inflammation.
  • Item 9 The method according to any one of Items 87 to 90, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 92 The method according to Item 91, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 9 The method according to any one of Items 87 to 95, wherein the cancer is an enteritis-related cancer in ulcerative colitis.
  • Item 9 The method according to any one of Items 87 to 97, wherein the inhibitor inhibits the nuclear translocation of NFKBIZ.
  • Item 9 The method according to any one of Items 87 to 98, wherein the inhibitor inhibits the binding between NFKBIZ and p50.
  • Item 10 The method according to any one of Items 87 to 100, wherein the inhibitor has an E3 ligase inhibitory activity.
  • Item 10 The method according to any one of Items 87 to 101, wherein the inhibitor is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 10 The method according to Item 102, wherein the inhibitor is a nucleic acid.
  • Item 105 The method according to Item 102, wherein the inhibitor is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Treatment and / or treatment of cancer including a Legnes 1 enhancer, characterized in that it is administered to a subject with reduced expression of Legnes 1 and / or decreased activity of Legnes 1.
  • a pharmaceutical composition for prevention is provided.
  • a subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • Item 10 The composition according to Item 107, which is determined by a step including a step.
  • Item 110 The composition according to Item 109, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 11 The composition according to Item 110, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • composition according to Item 113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 16 The composition according to any one of Items 107 to 115, wherein the enhancer enhances the activity of Legnes 1.
  • Item 17 The composition according to any one of Items 107 to 116, wherein the enhancer inhibits a legnes monodegrading enzyme.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 119 The composition according to any one of Items 107 to 118, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 120 The composition according to any one of Items 107 to 119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 12 The composition according to Item 120, wherein the enhancer is a nucleic acid.
  • Item 122 The composition according to Item 120, wherein the enhancer is an antibody.
  • Item 123 The composition according to Item 120, wherein the enhancer is a low molecular weight compound.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of legnes 1 quantified in (1) with the expression and / or activity of legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • the Legnes 1 enhancer for use according to item A107 characterized in that it is determined in a process that includes a process.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer,
  • Item A114 Legnes 1 for use according to item A113, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer. Enhancer.
  • legnes 1 enhancer for use according to any one of items A107 to 115, wherein the enhancer enhances the activity of legnes 1.
  • legnes 1 enhancer for use according to item A117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • legnes 1 enhancer for use according to any one of items A107 to A118, wherein the enhancer has an E3 ligase inhibitory activity.
  • the legnace 1 enhancer for use according to any one of items A107 to A119, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • legnes 1 enhancer for use according to item A120, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • a method for treating and / or preventing cancer in a subject which comprises the step of administering an effective amount of Legnes 1 enhancer to the subject, and the subject has decreased expression of Legnes 1. / Or a method in which the activity of legnes 1 is reduced.
  • [Item B108] (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • the method of item B107 further comprising a step.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer,
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item B118 The method according to Item B117, wherein the legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-. Ill) -the method of item B123, which is benzoic acid (GS143).
  • legnes 1 enhancer in the manufacture of a drug for the treatment and / or prevention of cancer, wherein the drug has reduced expression of legnes 1 and / or activity of legnes 1.
  • Use characterized by being administered to a declining subject.
  • a subject whose expression of Legnes 1 is reduced and / or whose activity of Legnes 1 is reduced is (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased.
  • Item 6 The use according to item C107, which is determined in a process including the process.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer,
  • colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • Il -the use according to item C123, which is benzoic acid (GS143).
  • a method for predicting the effectiveness of a Legnes 1 enhancer on a subject which comprises measuring the expression and / or activity of Legnes 1 in the cancer cells of the subject.
  • Item 126 Measurement of the expression and / or activity of Legnes 1 in the cancer cells (1) A step of measuring the expression and / or activity of Legnes 1 in cancer cells obtained from the subject. (2) A step of comparing the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and ( 3) Based on the results of (2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it is determined that the expression and / or activity of legnes 1 is decreased. Item 125. The method according to Item 125, which is determined by a step including the step.
  • Item 128 The method according to Item 127, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 129 The method according to Item 128, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant mel
  • Item 132 The method of item 131, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 137 The method according to any one of Items 125 to 136, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 138 The method according to any one of Items 125 to 137, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 139 The method according to Item 138, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • [Item 143] A method for screening a Legnes 1 enhancer. (1) A step of measuring the expression and / or activity of Legnes 1 without allowing an enhancer candidate to act on cancer cells. (2) A step of measuring the expression and / or activity of Legnes 1 after allowing the enhancer candidate to act on the cancer cells, and when the results of (3) and (2) are larger than the results of (1). In addition, a step of determining the enhancer candidate as a legnace 1 enhancer, Including methods.
  • a method for screening a therapeutic and / or preventive agent for cancer (1) A step of measuring the expression and / or activity of Legnes 1 without allowing a therapeutic and / or prophylactic agent candidate to act on cancer cells. (2) The steps of measuring the expression and / or activity of Legnes 1 after allowing the therapeutic and / or prophylactic agent candidate to act on the cancer cells, and the results of (3) and (2) are the results of (1). A step of determining the therapeutic and / or prophylactic agent candidate as a cancer therapeutic and / or prophylactic agent if it is greater than the result. Including methods.
  • (1) A step of measuring the activity of Legnes 1 without allowing a test substance to act on cancer cells.
  • (2) The step of measuring the activity of Regnes 1 after allowing the test substance to act on the cancer cells, and when the results of (3) and (2) are larger than the results of (1), the test is performed.
  • Item 147 The method according to Item 146, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item 148 The method according to Item 147, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular embryonic cell tumor, ovarian embryonic cell tumor, Wilms tumor, skin cancer, mal
  • Item 15 The method according to Item 150, wherein the colorectal cancer comprises at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, and anal cancer.
  • Item 153 The method according to any one of Items 143 to 152, wherein the enhancer enhances the activity of Legnes 1.
  • Item 154 The method according to any one of Items 143 to 153, wherein the enhancer inhibits a legnes monodegrading enzyme.
  • legnes 1 degrading enzyme is a legnes 1 kinase or a legnes 1 ubiquitinizing enzyme.
  • Item 156 The method according to any one of Items 143 to 155, wherein the enhancer has an E3 ligase inhibitory activity.
  • Item 157 The method according to any one of Items 143 to 156, wherein the enhancer is a nucleic acid, an antibody, a low molecular weight compound, or a high molecular weight compound.
  • Item 158 The method according to Item 157, wherein the enhancer is a nucleic acid.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-.
  • the E3 ligase inhibitor for use according to item D1 wherein the cancer is a cancer associated with chronic inflammation.
  • the E3 ligase inhibitor for use according to item D2 wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from
  • E3 ligase inhibitor for use according to any one of items D1 to D4.
  • the low molecular weight compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl). )-Benzoic acid (GS143), an E3 ligase inhibitor for use according to item D12.
  • E1 The use of an E3 ligase inhibitor in the manufacture of a drug for the treatment and / or prevention of cancer, wherein the drug has increased expression of E3 ligase and / or activity of E3 ligase. Use, characterized by being administered to subjects with elevated levels.
  • Item E2 The use according to Item E1, wherein the cancer is a cancer associated with chronic inflammation.
  • Item E3 The use according to Item E2, wherein the cancer associated with the chronic inflammation is a cancer associated with inflammatory bowel disease.
  • Item E4 The use according to Item E3, wherein the inflammatory bowel disease is ulcerative colitis.
  • the cancers are colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, Head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thoracic adenoma / thoracic adenocarcinoma, breast cancer, gastric cancer, cholecyst / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreas Gastrointestinal stromal tumor, villous epithelial cancer, uterine body cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, urinary tract epithelial cancer, renal cancer, renal cell cancer, Includes at least one selected from the group consisting of testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, skin cancer, malignant lymphoma, plasma
  • NFKBIZ inhibitors of the present disclosure are effective in the treatment and / or prevention of cancer, particularly in the treatment and prevention of colorectal cancer. / Or effective for prevention.
  • the Regnes 1 enhancer of the present disclosure (for example, a substance that enhances the activity of Legnes 1) is effective for the treatment and / or prevention of cancer, and is particularly effective for the treatment and / or prevention of colorectal cancer.
  • a substance that reduces the expression level of NFKBIZ (for example, a substance that reduces the expression level of NFKBIZ, and / or a substance that suppresses the function of NFKBIZ) by measuring the gene expression and / or activity of NFKBIZ in cancer cells derived from a subject. ) Can be predicted for effective patients.
  • a Regnes 1 enhancer for example, a substance that enhances the activity of Legnes 1
  • a patient for whom a Regnes 1 enhancer for example, a substance that enhances the activity of Legnes 1 is effective by measuring the expression and / or activity of Legnes 1 in cancer cells derived from a subject. it can.
  • NFKBIZ inhibitors for example, substances that reduce the expression level of NFKBIZ and / or substances that suppress the function of NFKBIZ
  • NFKBIZ inhibitors that are effective in treating and / or preventing cancer can be selected. ..
  • a Legnes 1 enhancer for example, a substance that enhances the activity of Legnes 1 that is effective for the treatment and / or prevention of cancer.
  • FIG. 1 plots the number of mutations within the entire exon region in a single crypt in subjects without ulcerative colitis (non-UC subjects) and subjects with ulcerative colitis (UC subjects) against the age of the subjects. It is a figure.
  • the regression line for section 0 is drawn for samples from non-UC subjects.
  • the p-value indicates significance for the difference between non-UC and UC subjects (Bilateral Mann-Whitney U test).
  • FIG. 2 is a diagram showing the distribution of NFKBIZ, PIGR, ZC3H12A and TRAF3IP2 mutations in normal mucosa (above each domain diagram) and CAC (below each domain diagram).
  • FIG. 1 plots the number of mutations within the entire exon region in a single crypt in subjects without ulcerative colitis (non-UC subjects) and subjects with ulcerative colitis (UC subjects) against the age of the subjects. It is a figure.
  • the regression line for section 0 is drawn for samples from non-UC subjects.
  • FIG. 2 is a diagram further showing a hotspot mutation in the DSGxxS motif of the ZC3H12A gene.
  • FIG. 4 is a diagram showing mutations in the IL-17 signaling pathway observed in the normal mucosa (UC normal mucosa) of ulcerative colitis. Genes with mutations detected in UC normal mucosa are shown in gray squares.
  • FIG. 4 is a diagram showing mutations in the IL-17 signaling pathway observed in the normal mucosa (UC normal mucosa) of ulcerative colitis. Genes with mutations detected in UC normal mucosa are
  • FIG. 6 shows the knockdown efficiency (left panel) and growth curve (right panel) of NFKBIZ measured by real-time PCR for two human colon cancer cell lines (HT29, HCT116) treated with NFKBIZ and control shRNA. It is a figure.
  • FIG. 7 is a diagram showing the experimental schedule of CAC induction in Nfkbiz fl / fl VilCre (Nfkbiz cKO) and Nfkbiz fl / fl (control) mice.
  • Azoxymethane (AOM) administration was followed by 3 cycles of sodium dextran sulfate (DSS) administration (ip: intraperitoneal administration).
  • FIG. 8 is a diagram showing typical examples of AOM-DSS-induced colon tumors in control (top) and Nfkbiz cKO (bottom) mice.
  • FIG. 9 shows a box plot of the number of tumors by tumor size (diameter) (left) and a box plot of total tumor volume (right). Tumor sizes that showed a marked difference between Nfkbiz cKO and control were indicated by asterisks (bidirectional Mann-Whitney U test; p ⁇ 0.05). In addition, the significance of the difference in total tumor volume was indicated by a P value (Bidirectional Mann-Whitney U test; p ⁇ 0.05).
  • FIG. 9 shows a box plot of the number of tumors by tumor size (diameter) (left) and a box plot of total tumor volume (right). Tumor sizes that showed a marked difference between Nfkbiz cKO and control were indicated by asterisks (bidirectional Mann-Whitney U test; p ⁇ 0.05). In addition, the significance of the difference in total
  • FIG. 10 is a diagram showing that GS143, which is an E3 ligase inhibitor, suppresses the mRNA expression level of NFKBIZ in the HT29 cell line.
  • uM represents ⁇ M.
  • FIG. 11 shows that GS143, an E3 ligase inhibitor, increases the expression level of Legnes 1 in the HT29 cell line. The upper and lower rows show the results of Western blotting, respectively, and the middle row shows the expression level ratio of Legnes 1 and ⁇ -tubulin.
  • FIG. 12 is a diagram showing that GS143, which is an E3 ligase inhibitor, exhibits a concentration-dependent cell growth inhibitory effect on the HT29 cell line. uM represents ⁇ M.
  • the expression level is shown as a relative value with the expression level of the control mouse as 1.
  • NFKBIZ inhibitor includes any substance, factor, means, etc. that inhibits NFKBIZ in some way.
  • NFKBIZ inhibitors typically include substances that reduce the expression level of NFKBIZ, substances that suppress the function of NFKBIZ, etc.
  • measures may be taken to prevent NFKBIZ from functioning or not being expressed as a result. It may be a possible means (including, for example, a means for realizing genome editing) or the like.
  • NFKBIZ NF-kappa-B inhibitor zeta
  • the NFKBIZ gene belongs to the ankyrin-repeat family (ankyrin repeat family) and is known to be induced by lipopolysaccharide.
  • NFKBIZ is known to play a role in the inflammatory response to LPS by interacting with the NF-B protein via the ankyrin repeat domain (Gudrun Totzke et al. J Biol Chem. 281: 12645-12654 (2006). )).
  • the function of NFKBIZ when the function of NFKBIZ is suppressed, the development of cancer is suppressed and the growth of the developed cancer is suppressed.
  • NFKBIZ inhibitors can be used in the treatment and / or prevention of cancer.
  • One embodiment of the present disclosure may provide a composition comprising an NFKBIZ inhibitor.
  • the NFKBIZ inhibitor has been found to be effective against cancers arising from inflammatory diseases (Examples), and the NFKBIZ inhibitor is highly probable for cancers that are not accompanied by inflammation. It can be said that it is effective.
  • NFKBIZ inhibitor examples include a substance that reduces the expression level of NFKBIZ and a substance that suppresses the function of NFKBIZ, but the NFKBIZ inhibitor also includes a combination of a plurality of substances that realize inhibition of NFKBIZ.
  • the NFKBIZ inhibitor include, for example, means for genetically modifying to inhibit NFKBIZ, cells having an activity of inhibiting NFKBIZ, and the like.
  • “Reducing the expression level of NFKBIZ” means reducing the expression level of the protein related to NFKBIZ.
  • examples of the “substance that reduces the expression level of NFKBIZ” include “nucleic acid”, “antibody”, “low molecular weight compound” and “high molecular weight compound”.
  • Preferred examples of the “substance that reduces the expression level of NFKBIZ” include “nucleic acid”, “antibody”, and “low molecular weight compound”. More preferably, “nucleic acid” and “low molecular weight compound” are mentioned as “substances that reduce the expression level of NFKBIZ".
  • a “small molecule compound” is more preferable as the "substance that reduces the expression level of NFKBIZ”.
  • “Suppressing the function of NFKBIZ” means inhibiting or eliminating the function of NFKBIZ.
  • As an embodiment of inhibition or disappearance of the function of NFKBIZ for example, “inhibiting the nuclear translocation of NFKBIZ”, “inhibiting the binding between NFKBIZ and p50", and “a transcription factor consisting of a complex containing NFKBIZ” , Inhibiting interaction with a specific DNA sequence.
  • “Inhibiting the nuclear translocation of NFKBIZ” can be confirmed, for example, by using the Western Blot method using a cell lysate of cytoplasm and nuclear fraction in cells on which an inhibitor candidate is acted.
  • “Inhibiting the binding between NFKBIZ and p50” can be confirmed, for example, by immunoprecipitation with an anti-NFKBIZ antibody or an anti-p50 antibody in cells on which an inhibitor candidate is acted.
  • “Inhibiting a transcription factor consisting of a complex containing NFKBIZ from interacting with a specific DNA sequence” means, for example, amplifying an anti-NFKBIZ antibody and its specific DNA sequence in cells on which an inhibitor candidate is acted. It can be confirmed by the CHIP-PCR method using a possible primer.
  • Examples of the "substance that suppresses the function of NFKBIZ” include "nucleic acid", “antibody”, “low molecular weight compound” and "high molecular weight compound”.
  • NFKBIZ neuropeptide-binding protein
  • “substance that suppresses the function of NFKBIZ” include “nucleic acid”, “antibody”, and “low molecular weight compound”. More preferably, “substances that suppress the function of NFKBIZ” include “antibodies” and “small molecule compounds”. More preferably, a "low molecular weight compound” is mentioned as the "substance that suppresses the function of NFKBIZ".
  • reducing the expression level of NFKBIZ and “suppressing the function of NFKBIZ” may be collectively referred to as “suppressing the expression and / or function of NFKBIZ”.
  • the "Regnes 1 enhancer” includes any substance, factor, means, etc. that promotes the action of Legnes 1 in some way.
  • the legnes 1 enhancer typically includes a substance that enhances the expression of legnes 1, a substance that enhances the activity of legnes 1, and the like, and other measures that increase the function or expression of legnes 1 as a result. It may be a means that can be taken (including, for example, a means for realizing genome editing).
  • the Legnes 1 enhancer has been found to be effective against cancers arising from inflammatory diseases (Examples), and the Legnes 1 enhancer is also high against non-inflammatory cancers. It can be said that it is effective with a probability.
  • Regnase 1 (hereinafter, also referred to as Regnase-1, Regnase-1, ZC3H12A, or Zc3h12a) is a member of the CCCH zinc finger protein family having RNAse activity, and has post-transcriptional regulatory activity via degradation of target mRNA. It is an RNA-binding protein that mediates. Regnes 1 has been reported to be an RNase associated with immune disorders by directly controlling the stability of inflammatory genes (Kazufumi Matsushita et al. Nature 458: 1185-1190. (2009)). In addition, it has been reported that the dysfunction of Legnes 1 leads to the rapid onset of abnormal hematopoiesis (Hiroyasu Kidoya et al. Nature Communications 10: 1-16. (2019)).
  • legnes 1 has been reported to bind to the 3'UTR of NFKBIZ mRNA and promote its degradation (Gesine Behrens et al. Nucl Acids Res, 46: 4256 (2016)). Furthermore, it has been reported that legnes 1 can be degraded by SCF ⁇ -TrCP1- mediated ubiquitination by phosphorylation of phosphorylation sites S438 and S442 by an IKK (enzyme I ⁇ B kinase) complex (SCF ⁇ -TrCP1 mediated ubiquitination). Hidenori Iwasaki et al. Nature Immunology, 12: 1167-1175. (2011)).
  • legnes 1 enhancer examples include substances that increase the expression of legnes 1 and substances that promote the function of legnes 1, but the legnes 1 enhancer also includes a combination of a plurality of substances that realize an increase in the action of legnes 1.
  • Examples of the Legnes 1 enhancer include, for example, means for genetically modifying the expression of Legnes 1 and cells having an activity of enhancing the activity of Legnes 1.
  • enhancing the activity of legnes 1 is meant enhancing the RNase activity of legnes 1.
  • the “substance that enhances the activity of legnes 1” include “a substance that increases the expression level of legnes 1” and “a substance that inhibits legnes 1 degrading enzyme”, and preferably “a substance that inhibits legnes 1 degrading enzyme”.
  • “Substance” can be mentioned.
  • Examples of “substances that enhance the activity of legnes 1", “substances that increase the expression level of legnes 1", or “substances that inhibit legnes 1 degrading enzyme” include “nucleic acid", “antibody”, and “low molecular weight compound”. And “polymer compounds”.
  • the “substances that enhance the activity of legnes 1", the “substances that increase the expression level of legnes 1", or the “substances that inhibit the legnes 1 degrading enzyme” are preferably “nucleic acid”, “antibody”, and “low”.
  • "Molecular compound” can be mentioned. More preferably, “antibodies” and “low molecular weight compounds” are used as "substances that enhance the activity of legnes 1", “substances that increase the expression level of legnes 1", or “substances that inhibit legnes 1 degrading enzymes”. Can be mentioned. More preferably, "low molecular weight compound” is mentioned as "a substance that enhances the activity of Legnes 1", “a substance that increases the expression level of Legnes 1", or “a substance that inhibits a legnes 1 degrading enzyme”.
  • Legnes 1 degrading enzyme means an enzyme that decomposes legnes 1, and examples thereof include “legnes 1 kinase” that phosphorylates legnes 1 and “legnes 1 ubiquitinifying enzyme” that ubiquitinates legnes 1. ..
  • the NFKBIZ inhibitor and / or Legnes 1 enhancer may have E3 ligase inhibitory activity.
  • E3 ligase inhibitory activity is defined. It is understood that NFKBIZ inhibitors and / or ligase 1 enhancers with can be used for the treatment and / or prevention of cancer.
  • E3 ligase inhibition refers to ubiquitin-bound E2 ubiquitin ligase, which recognizes the substrate of the protein, assists in the transfer of ubiquitin from E2 to the substrate, or inhibits the function of E3 ubiquitin ligase that catalyzes directly. Means to do.
  • NFKBIZ inhibitor / Legnes 1 enhancer an NFKBIZ inhibitor and a Legnes 1 enhancer
  • NFKBIZ inhibitor / Legnes 1 enhancer An example of the NFKBIZ Inhibitor / Legnes 1 Enhancer is the GS143 described in the examples herein.
  • E3 ligase inhibitor includes any substance, factor, means, etc. that inhibits the action of E3 ligase in some way.
  • the E3 ligase inhibitor typically includes a substance that reduces the expression of E3 ligase, a substance that reduces the activity of E3 ligase, and the like, and other measures that reduce the function or expression of E3 ligase as a result. It may be a means that can be taken (including, for example, a means for realizing genome editing).
  • E3 ligase is also referred to as E3 ubiquitin ligase.
  • E3 ligase inhibitor examples include “nucleic acid”, “antibody”, “low molecular weight compound” and “high molecular weight compound”.
  • Preferred examples of the “E3 ligase inhibitor” include “nucleic acid”, “antibody”, and “small molecule compound”. More preferably, the “E3 ligase inhibitor” includes an “antibody” and a “small molecule compound”. More preferably, the “E3 ligase inhibitor” includes a "low molecular weight compound”.
  • a low molecular weight compound that inhibits E3 ligase is referred to as an "E3 ligase inhibitory compound".
  • E3 ligase inhibitory compound As an example of the E3 ligase inhibitor, GS143 described in the examples of the present specification can be mentioned.
  • E3 ligase inhibitors suppress the development and growth of cancer
  • E3 ligase inhibitors are used to treat cancer and to treat cancer. / Or it is understood that it can be used for prevention.
  • Nucleic acid means a molecule in which nucleotides consisting of bases, sugars and phosphates are linked by phosphodiester bonds, and contains ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), and is artificially modified or substituted nucleic acid.
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • nucleic acid precursors that are converted to nucleic acids in vivo Artificially modified or substituted nucleic acids include 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6 and O-6 substituted purines (including 2-aminopropyladenine), 5-propynyl. Included include uracil and 5-propynylcytosine and the like.
  • nucleic acid As the artificially modified or substituted nucleic acid, the 2'position and the 4'position of the nucleic acid are linked (crosslinked), and the nucleic acid has two ring structures (bicyclic type). Nucleic acid (crosslinked nucleic acid (BNA)) and the like can also be used. In addition, modified nucleic acids such as peptide nucleic acids, locked nucleic acids, morpholinon nucleic acids, and thionucleic acids can be used. Examples of the "nucleic acid” include “antisense nucleic acid", “ribozyme nucleic acid” and "nucleic acid having RNAi activity”.
  • nucleic acid examples include “antisense nucleic acid” and “ribozyme nucleic acid”.
  • examples of the “nucleic acid” include “antisense nucleic acid” and “nucleic acid that causes RNAi activity”.
  • examples of the nucleic acid that causes RNAi activity include one or more combinations of siRNA, shRNA, miRNA, short or long chain RNA, or modifications thereof.
  • the "anti-NFKBIZ antibody” means an antibody that specifically recognizes NFKBIZ, and means an antibody that has a binding activity to NFKBIZ.
  • the "antibody that specifically recognizes NFKBIZ” may be either a monoclonal antibody or a polyclonal antibody.
  • Preferred examples of the "antibody that specifically recognizes NFKBIZ” include a polyclonal antibody. More preferably, a mammalian-derived monoclonal antibody is mentioned as the "antibody that specifically recognizes NFKBIZ".
  • Monoclonal and polyclonal antibodies derived from mammals are those produced in animal blood, those produced in hybridomas, and those produced in hosts transformed with an expression vector containing an antibody gene by genetic engineering techniques.
  • Optimal antibodies are screened from a vast library of 1 trillion molecules by phage display and mass-produced by CHO cells from that gene, and humans obtained directly from transgenic mice that produce human antibodies. Examples include antibodies. Monoclonal antibodies and polyclonal antibodies can be produced by methods known to those skilled in the art.
  • the "low molecular weight compound” means an "organic low molecular weight compound” or an “inorganic low molecular weight compound” having a molecular weight of less than 10,000.
  • the "low molecular weight compound” is preferably an "organic low molecular weight compound”.
  • the molecular weight of the "low molecular weight compound” is preferably 5000 or less, more preferably 3000 or less, still more preferably 2000 or less, and most preferably 1000 or less.
  • a preferred embodiment of the NFKBIZ inhibitor and / or Regnes 1 enhancer is a low molecular weight compound "E3 ligase inhibitor compound”.
  • E3 ligase inhibitory compound examples include the compounds described in International Publication 2006/129583. Specifically, as an "E3 ligase inhibitor compound", 4- (3-Benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-1-yl) -benzoic acid (GS143), ( 5-[[3-Dimethylamino) propyl] Amino] -3,10-Dimethylpyrimidino [4,5-b] Quinoline-2,4 (3H, 10H) -dione dihydrochloride (HLI373, 502137-98- 6) and [(1R, 2R, 4R, 6R, 8S, 9E, 11R) -8-hydroxy-4,9-dimethyl-14-methylidene-13-oxo-5,12-dioxatricyclo [9.
  • E3 ligase inhibitor compound is 4- (3-benzyl-4- (5- (2-fluoro-phenyl) -furan-2-ylmethylene) -5-oxo-4,5-dihydropyrazole-.
  • 1-yl) -benzoic acid can be mentioned.
  • GS143 has been found to be effective against cancers arising from inflammatory diseases (Examples), and GS143 is also highly probable to be effective against non-inflammatory cancers. It can be said that there is.
  • the "polymer compound” means a compound having a molecular weight of 10,000 or more.
  • Examples of the “polymer compound” include “natural polymer”, “synthetic polymer”, and “semi-synthetic polymer”.
  • Examples of the “natural polymer” include polyamine, some lipids, cellulose, amylose, starch, chitin, natural rubber, polypeptides, proteins, DNA, RNA, some lipids, lignin, asphaltene and the like.
  • Examples of the "synthetic polymer” include polymers. Examples of the “semi-synthetic polymer” include artificial cellulose and the like.
  • the “substance” in the present disclosure may exist in the form of a hydrate and / or a solvate, the hydrate and / or the solvate is also included in the disclosed compounds.
  • the substances in the present disclosure may optionally be used in their pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salt” means a salt prepared from a pharmaceutically non-toxic acid (including inorganic and organic acids).
  • Pharmaceutically acceptable salts include, for example, but not limited to acetates, alginates, anthranylates, benzenesulfonates, benzoates, camphorsulfonates, citrates, ethenesulfonates, formic acids.
  • Salt fumarate, gluconate, glutamate, glucolenate, galacturonate, glycidate, hydrobromide, hydrochloride, ISEthionate, lactate, maleate, malate, mandel Acids, methanesulfonates, mutinates, nitrates, pamoates, pantothenates, phenylacetates, propionates, phosphates, salicylates, stearate, succinates, sulfanylates, sulfates Examples include salts, tartrates, and p-toluene sulfonates.
  • Preferred examples of the pharmaceutically acceptable salt include hydrobromide salt and hydrochloride. The most preferred pharmaceutically acceptable salt is hydrochloride.
  • the present disclosure may provide treatment of cancer with the above-mentioned inhibitors and / or enhancers. Cancers, especially those associated with chronic inflammation, can be targeted. Without wishing to be bound by theory, in the examples herein, the driver genes for cancer in chronic inflammation have been identified and the inhibitors and / or enhancers described above are effective in controlling such cancers. Is understood.
  • the present disclosure may cover diseases having characteristics such as those exemplified below.
  • Chronic inflammation means a state in which the activities of inflammatory substances, cells, etc. do not converge even though the tissue abnormality has been resolved.
  • a chronic inflammatory disease for example, "inflammatory bowel disease (IBD; inflammatory bowel disease)" can be mentioned.
  • “Inflammatory bowel disease” is a general term for diseases related to chronic inflammation that causes inflammation of the gastrointestinal tract, and is a disease that causes inflammation of the intestine by causing abnormalities in the immune system and autoimmune cells attacking intestinal cells. means. Symptoms of "inflammatory bowel disease” include “diarrhea”, “bloody stool”, and “abdominal pain”. Examples of the “inflammatory bowel disease” include “ulcerative colitis (UC)” and “Crohn's disease” (CD: Crohn's disease). Preferred examples of the "inflammatory bowel disease” include “ulcerative colitis”.
  • Ulcerative colitis means a non-specific inflammatory disease of unknown cause, which mainly causes ulcers and erosions on the mucosa of the large intestine.
  • Ulcerative colitis includes “ulcerative (chronic) colitis”, “ulcerative (chronic) colitis”, “ulcerative (chronic) rectal sigmoid colitis", "inflammatory polyp", Examples include “left side colitis”, “other ulcerative colitis” and “ulcerative colitis of unknown cause”.
  • Symptoms of "ulcerative colitis” include "mucous stool”, “diarrhea”, “fever” / "weight loss”, "abdominal pain” and "anemia”.
  • ulcerative colitis Complications of "ulcerative colitis” include "erythema nodosum”, “polyarthritis”, “chilblains”, “pyoderma gangrenosum”, “perianal inflammation / anorectal abscess”, “anorectal abscess” Ulcerative colitis, addictive giant colitis, perforation, pseudopolyarthritis (polyp), gingitis, stomatitis, chilblains (feet, fingers, ears), edema , "Thirst", and “Cancer".
  • Examples of the "carcinogenesis associated with ulcerative colitis” include “enterocolitis-related cancer (CAC) in ulcerative colitis”.
  • “Crohn's disease” means an inflammatory disease of unknown cause that causes discontinuous chronic granulomatous inflammation, primarily in the entire gastrointestinal tract from the oral cavity to the anus.
  • Examples of “Crohn's disease” include “Crohn's disease of the small intestine”, “Crohn's disease of the large intestine”, “Other Crohn's disease” and “Crohn's disease of unknown details”.
  • Symptoms of "Crohn's disease” include "abdominal pain”, “diarrhea”, “fever”, “weight loss”, "anal fistula (anal fistula, anal fissure, anal ulcer, etc.)” and “vomiting".
  • Complications of "Crohn's disease” include “joint symptoms (arthralgia, arthritis)", “skin symptoms (erythema nodosum, pyoderma gangrenosum)", “Sweet disease”, and “eye symptoms (iriditis)”. , “Primary sclerosing cholangitis” and “malignant tumor (colon cancer, ileal cancer)”.
  • Cancer in this disclosure means a malignant tumor.
  • Cancer includes, for example, colon cancer, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, true polyemia, malignant lymphoma, plasma cell tumor, multiple myeloma, myelodystrophy syndrome, brain tumor, etc.
  • the present disclosure may cover cancers that include at least one selected from the group including those described above.
  • the “cancer” is preferably “colon cancer”.
  • colonal cancer examples include “cecal cancer”, “colon cancer”, “rectal cancer”, and “anal cancer”. Preferred examples of “colorectal cancer” include “colon cancer”, “rectal cancer”, and “anal cancer”. More preferably, “colorectal cancer” includes “colon cancer” and “rectal cancer”. More preferably, “colon cancer” is mentioned. Colorectal cancers, including at least one selected from the group consisting of cecal cancer, colon cancer, rectal cancer, or anal cancer, may be included in the present disclosure.
  • the "cancer” is preferably “cancer associated with chronic inflammation”.
  • “Cancer associated with chronic inflammation” refers to cancer that develops with the onset of chronic inflammation and is diagnosed as cancer associated with chronic inflammatory disease.
  • “Cancer associated with chronic inflammation” includes, for example, pancreatic cancer associated with inflammatory bowel disease, esophageal cancer associated with reflux esophagitis, liver cancer associated with alcoholic hepatitis, and non-alcoholic steatohepatitis. Examples include liver cancer associated with liver cancer, gastric cancer associated with chronic gastric inflammation, pancreatic cancer associated with chronic pancreatitis, and cholangiocarcinoma associated with primary sclerosing cholangitis.
  • the "cancer associated with chronic inflammation” preferably includes colon cancer associated with inflammatory bowel disease.
  • the "cancer associated with chronic inflammation” more preferably includes colon cancer associated with ulcerative colitis. More preferably, “cancer associated with chronic inflammation” includes "enterocolitis-related cancer in ulcerative colitis (CAC)” and "colon cancer in ulcerative colitis”.
  • CAC ulcerative colitis
  • Enterocolitis-related cancer or "inflammatory cancer” means "colon cancer associated with inflammatory bowel disease”.
  • NFKBIZ deficient mutation suppresses the production of tissue inflammatory cytokines in a mouse enteritis model and alleviates enteritis associated with tissue destruction and regeneration.
  • a composition comprising an NFKBIZ inhibitor and / or a Regnes 1 enhancer for suppressing the production of inflammatory cytokines, or use thereof, may be provided.
  • a composition comprising an NFKBIZ inhibitor and / or a Regnes 1 enhancer, or use thereof, may be provided to alleviate enteritis associated with tissue destruction and regeneration.
  • prevention is an act of administering the active ingredient of the present disclosure to a person who has not been diagnosed as developing the target disease, for example, to prevent the onset of the disease. Is the purpose.
  • treatment is an act of administering the active ingredient of the present disclosure to a person (patient) diagnosed as having a disease by a doctor, for example, reducing the disease or symptom.
  • the purpose is to prevent the growth of carcinoma or to return it to the state before the onset of the disease.
  • the purpose of administration is to prevent the exacerbation of diseases and symptoms or the growth of carcinoma, if the administration is to a patient, it is a therapeutic act.
  • the amount used varies depending on the symptoms, age, administration method, etc., but for example, in the case of intravenous injection, the lower limit per day is set for adults.
  • the effect is expected by administering 0.01 mg (preferably 0.1 mg) and, as the upper limit, 1000 mg (preferably 100 mg) in one or several divided doses according to the symptom.
  • the administration schedule include single administration, once daily administration for 3 days, or twice daily administration for 1 week. Further, each of the above-described administration methods can be repeated at intervals of about 1 day to about 60 days.
  • the inhibitors and / or enhancers of the present disclosure can be formulated and administered directly or in an appropriate dosage form by oral administration or parenteral administration.
  • Dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, haptics and the like. Formulations are made by known methods using pharmaceutically acceptable additives.
  • Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweetness, depending on the purpose. Agents, fragrances and the like can be used.
  • Specific examples of the additive include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl. Examples thereof include alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide and talc.
  • inhibitors and / or enhancers of the present disclosure can be administered by parenteral administration or oral administration, but are preferably administered by an oral method.
  • the effectiveness of the NFKBIZ inhibitor on the subject can be predicted by measuring the gene expression of NFKBIZ and / or the activity of NFKBIZ in the cancer cells of the subject.
  • subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ shall be the subject of pharmaceutical compositions or methods for treating and / or preventing cancer. Can be done.
  • the NFKBIZ inhibitor can be used in subjects with increased expression of NFKBIZ and / or increased activity of NFKBIZ.
  • the increased expression of NFKBIZ and / or the increased activity of NFKBIZ means that (1) the expression and / or activity of the NFKBIZ gene in cancer cells obtained from the subject is measured, (2). Comparing the expression and / or activity of the NFKBIZ gene quantified in (1) with the expression and / or activity of the NFKBIZ gene (hereinafter referred to as a control value) in cells collected from a healthy subject, and (3) ( Based on the result of 2), when the expression and / or activity of the NFKBIZ gene quantified in (1) is larger than the control value, the expression of NFKBIZ is enhanced and / or the activity of NFKBIZ is increased. It can be determined in a process that includes determining that it is.
  • Features described elsewhere herein may optionally be employed as features relating to inhibitors, subjects, cell types, measurements, and the like.
  • the effectiveness of the Legnes 1 enhancer on the subject can be predicted by measuring the expression and / or activity of Legnes 1 in the cancer cells of the subject.
  • subjects with reduced expression of Legnes 1 and / or reduced activity of Legnes 1 are subject to pharmaceutical compositions or methods for treating and / or preventing cancer. can do.
  • the Legnes 1 enhancer has been found to be effective against cancers arising from inflammatory diseases (Examples). ), It is understood that the Legnese 1 enhancer can be used for subjects with reduced expression of Legnes 1 and / or decreased activity of Legnes 1.
  • Decreased expression of legnes 1 and / or decreased activity of legnes 1 means that (1) measurement of legnes 1 expression and / or activity of cancer cells obtained from a subject, (2) ) To compare the expression and / or activity of Legnes 1 quantified in (1) with the expression and / or activity of Legnes 1 (hereinafter referred to as a control value) in cells collected from a healthy subject, and (3) ( Based on the result of 2), when the expression and / or activity of legnes 1 quantified in (1) is smaller than the control value, it includes determining that the expression and / or activity of legnes 1 is decreased. It can be determined in the process.
  • Features described elsewhere herein may be incorporated as needed as features relating to enhancers, subjects, cell types, measurements and the like.
  • the inhibitors and / or enhancers of the present disclosure can be used in combination with other drugs for the purpose of enhancing their effects.
  • the inhibitors and / or enhancers of the present disclosure can be used in combination with drugs such as hormone therapies, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and agents that inhibit their receptor action. ..
  • drugs that can be used in combination with the inhibitors and / or enhancers of the present disclosure are abbreviated as concomitant drugs.
  • the inhibitors and / or enhancers of the present disclosure show excellent anticancer activity even when used as a single agent, but the effect can be further enhanced by using in combination with one or several of the above-mentioned concomitant drugs (multi-drug combination). It can be further enhanced or the patient's QOL can be improved.
  • hormoneal therapeutic agent examples include phosfestol, diethylstillbestrol, chlorotrianisen, medroxyprogesterone acetate, megestrol acetate, chlormaginone acetate, ciproterone acetate, danazol, dienogest, asoprisnil, allylestradiol, and guest.
  • Linon nomegestol, tadenan, mepartricin, raloxifene, olmeroxyphene, revolmeroxyphene, anti-estrogen (eg, tamoxyphene citrate, tremiphen citrate, etc.), pills, mepitiostane, testrolactone, aminoglutetiimide, LH- RH derivatives (LH-RH agonists (eg, goselelin acetate, busererin, leuprolerin, etc.), LH-RH antagonists), raloxifene, epithiostanol, ethinylestradiol sulfonate, aromatase inhibitors (eg, fadrozol hydrochloride, ana) Strozol, retrozol, exemestane, borozol, formestane, etc.), flutamide, bicalutamide, niltamide, androgen receptor antagonists (eg, appartamide
  • chemotherapeutic agent examples include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecular-targeted therapeutic agents, immunomodulators, and other chemotherapeutic agents. .. A typical example is described below.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosfamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, and mel.
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosin, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine octofusphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, etc.).
  • UFT doxiflulysine, carmofur, gallositabin, emitefur, capecitabine, etc.
  • aminopterin nerzarabin
  • leukoporin calcium tabloid
  • butocin forinate calcium
  • levofolinate calcium cladribine
  • emitefur fludalabine
  • gemcitabine hydroxycarpamid , Pyritrexim, idoxyuridine, mitogazone, thiazofurin, ambamustin, bendamstin, and DDS preparations thereof.
  • anticancer antibiotic examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, acralubicin hydrochloride, pyrarubicin hydrochloride, and hydrochloric acid.
  • examples thereof include epirubicin, neocartinostatin, misramycin, zarkomycin, cartinophylline, mittan, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof.
  • plant-derived anticancer agent examples include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, bindecine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and their DDS preparations. Can be mentioned.
  • Molecular targeted therapies include, for example, imatinib, gefitinib, erlotinib, sorafenib, dasatinib, snitinib, nirotinib, laparib, pazopanib, luxolitinib, crizotinib, bemurafenib, bandetanib, ponatib nib, vemurafenib, bandetanib, ponatib.
  • immunomodulator examples include lenalidomide and pomalidomide.
  • chemotherapeutic agents include sobzoxane.
  • BRM immunotherapeutic agent
  • pisibanil crestin, cisophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulator, granulocyte colony stimulator, erythropoietin, phosphotoxin, BCG vaccine, corinebacterium Umpalbum, levamisol, polysaccharide K, prochodazole, anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, Toll-like Receptors agonist (for example, TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.) Can be mentioned.
  • the cell growth factor in the drug that inhibits the action of the cell growth factor and its receptor may be any substance as long as it promotes cell growth, and is usually accepted by a peptide having a molecular weight of 20,000 or less. Factors that exert their effects at low concentrations by binding to the body. Specifically, EGF (epidermal growth factor) or a substance having substantially the same activity as it (for example, TGFalpha), insulin or a substance having substantially the same activity as it (for example, insulin, IGF (insulin-)).
  • EGF epidermal growth factor
  • TGFalpha a substance having substantially the same activity as it
  • insulin for example, insulin, IGF (insulin-)
  • FGF fibroblast growth factor
  • a substance having substantially the same assay for example, acidic FGF, basic FGF, KGK (keratinocite growth factor), FGF-10. Etc.
  • other cell growth factors for example, CSF (colory stemming factor), EPO (erythropoitin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derivted)
  • TGF-beta transforming growth factor beta
  • HGF hepatotic growth factor
  • VEGF vascular endotherial growth factor
  • hergulin angiopoetin, etc.
  • the substance of the present disclosure can be used in combination with "another therapeutic agent for inflammatory bowel disease” for the purpose of enhancing its effect and / or treating complications.
  • another therapeutic agent for inflammatory bowel disease that can be used in combination with the substance of the present disclosure.
  • “Other inflammatory bowel disease treatments” include salicylic acid, salazosulfapyridine, mesalazine, prednisolone, betamethasone, budesonide, methylprednisolone, hydrocortisone, infliximab, adalimumab, ustekinumab, sertrizumab, golimumab, tacrolimus, azathioprine. , Cyclosporine, tofacitinib, and vedrizumab.
  • the administration period of the substance of the present disclosure and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at different times. In addition, it may be a mixture of the substance of the present disclosure and a concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the substance of the present disclosure and the concomitant drug can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present disclosure.
  • it can be used in combination with drugs (combined drugs) such as antiemetics, sleep-inducing agents, and anticonvulsants.
  • NFKBIZ inhibitors can be used in the present disclosure. Since NFKBIZ functions in the inflammatory response by interacting with the NF ⁇ -B protein via the ankyrin repeat domain, NFKBIZ inhibitors can be used to reduce the expression level of NFKBIZ and reduce the stability of NFKBIZ.
  • One embodiment of the present disclosure may provide a method of screening to screen for substances that treat and / or prevent cancer. This is based, at least in part, on the finding by the present inventors that the NFKBIZ inhibitor exhibits a particular growth inhibitory effect on cancer.
  • Methods for screening for therapeutic and / or prophylactic agents for cancer include (1) measuring gene expression and / or activity without allowing therapeutic and / or prophylactic agent candidates to act on cancer cells, (2) relevant.
  • the steps of measuring gene expression and / or activity after applying the therapeutic and / or prophylactic agent candidate to cancer cells, and the results of (3) and (2) are smaller or larger than the results of (1).
  • the treatment and / or prophylaxis may include the step of determining that the treatment and / or prophylaxis is a cancer treatment and / or prophylaxis.
  • a gene described in the present specification such as NFKBIZ or Legnes 1 can be targeted.
  • Features described elsewhere herein may optionally be employed as features relating to inhibitors, enhancers, subjects, cell types, measurements, and the like.
  • the method is characterized as a method of screening for NFKBIZ inhibitors, (1) measuring gene expression and / or activity of NFKBIZ without allowing the candidate inhibitor to act on cancer cells, (2). After the cancer cell is allowed to act on the inhibitor candidate, the step of measuring the gene expression and / or activity of NFKBIZ, and when the results of (3) and (2) are smaller than the result of (1).
  • the inhibitor candidate may include a step of determining that it is an NFKBIZ inhibitor.
  • the method is characterized as a method of screening for substances that reduce the expression level of NFKBIZ and / or suppress the function of NFKBIZ, (1) without allowing the test substance to act on the cancer cells.
  • the test substance may include a step of determining that the test substance is a substance that reduces the expression level of NFKBIZ and / or a substance that suppresses the function of NFKBIZ.
  • the method is characterized as a method of screening a legnes 1 enhancer, (1) measuring the expression and / or activity of legnes 1 without allowing the enhancer candidate to act on the cancer cells, (2).
  • the enhancer candidate may include a step of determining that it is a Legnes 1 enhancer.
  • the method is characterized as a method of screening for a substance that enhances the activity of Legnes 1, (1) measuring the activity of Legnes 1 without allowing the test substance to act on the cancer cells, (1).
  • Pathological evaluation was performed by two pathologists based on Riddell's classification (Riddell, RH et al. Human Pathology 14: 931 (1983)), and the samples were "normal (non-dysplasia)" and "low degree dysplasia". It was divided into four groups: "formation”, “severe dysplasia” and “cancer”. Specimens obtained by endoscopic biopsy were cut to a size of approximately 4 mm 2 to obtain a single crypt sample as well as a bulk crypt sample. Samples were taken from the surgical specimens using a punch biopsy (BP-25F, Kai Industries) with a diameter of 2.5 mm (4.9 mm 2 ).
  • the WES library was prepared using SureSelect Human All Exon V5 (Agilent Technologies) or xGen Exome Research Panel (IDT), and the concentrated exon fragments were prepared using HiSeq 2500 or NovaSeq 6000 (Illumina) in HiSeq 2500 or NovaSeq 6000 (Illumina). It was sequenced in the same manner (Yoshida, K. et al. Nature 478: 64 (2011)). The target sequence depth was 100x and the actual depth was 133x. The average depth of germline control from 101 individuals was 140x. Mutation detection was performed in the same manner as previously reported using Genomen2 pipeline version 2.6 (https://genomon.readedocs.io/ja/latest/) (Yokoyama, A.
  • sequence reads were aligned with the human genome reference sequence (hg19) using Burrows-Wheeler Aligner version 0.7.8 with default parameter settings. PCR duplication was excluded using biobambam version 0.0.191 (https://github.com/gt1/biobambam). Somatic mutations were detected by excluding polymorphisms and sequence errors. To this end, Genomon2 was used to first exclude low quality, unreliable reads and variants using thresholds of (i) mapping quality ⁇ 20, (ii) base quality ⁇ 15.
  • UC normal mucosa In the normal mucosa (UC normal mucosa) associated with ulcerative colitis, a gene belonging to the IL-17 signal pathway and having a protein-shortened mutation was also regarded as a driver. A total of 20 genes were considered drivers in UC normal mucosa.
  • HeLa cell line uses DMEM medium (08459-64, Nacalai Tesque) supplemented with 10% FBS (fetal bovine serum) and 100 ⁇ M 2-mercaptoethanol (21418-42, Nacalai Tesque). And maintained.
  • FBS fetal bovine serum
  • 2-mercaptoethanol 21418-42, Nacalai Tesque
  • the HT29 and HCT116 cell lines were maintained in DMEM medium supplemented with 10% FBS.
  • a cDNA having a full-length wild-type or C-terminal shortened mutation (W453 *) of the human ZC3H12A gene encoding Legnes 1 was inserted into cDNA 3.1 (+) (V79020, Thermo Fisher) together with an N-terminal Myc tag sequence.
  • the S438L mutant Regnase-1 was created using the QuikChange Lightning Site-Directed Mutagenesis Kit (210319, Agilent).
  • somatic cell mutations per unit increased more than 3 times compared to the normal mucosa of non-UC subjects, which was significantly higher (Fig. 1).
  • Analysis of gene mutations detected in the normal mucosa of UC patients revealed significant mutations in 14 genes of NFKBIZ, PIGR, ZC3H12A, TRAF3IP2, HNRNPF, ARID1A, ARID1B, KRAS, TP53, RNF43, ETV6, FBXW7, BCOR and BCORL1.
  • was positively selected and was considered to be a driver mutation ("dN / dS>1.0" and "q ⁇ 0.05").
  • mutations for most genes were considered to be loss-of-function mutations because they caused protein shortening.
  • Fig. 2 The exceptions were the ZC3H12A, HNRNPF and KRAS genes, which were considered function-acquired mutations because they formed hotspots where missense mutations were concentrated in some amino acids (Fig. 2).
  • the NFKBIZ, PIGR, ZC3H12A and TRAF3IP2 genes were mutually exclusive (Fig. 3). Since TRAF3IP2 was known to function as an adapter protein for the IL-17 signal pathway, analysis focusing on the IL-17 signal pathway revealed that the IL17RA, IL17RC, TRAF5, RELA, MAPK14 and BTRC genes were also shortened proteins.
  • the WES data (bam file) of a pair of tumors derived from patients with sporadic colorectal cancer (sCRC) and germline specimens is the The Cancer Genome Atlas (TCGA) Data Portal ( It was downloaded from https: //portal.gdc.cancer.gov/).
  • the bum file was converted to FASTQ format using biobambam, and mutation detection was performed using the same pipeline by the method applied to the fresh sample obtained in this study. For accuracy, sequence data obtained using WGA from tumors was excluded. Highly mutated tumors ( ⁇ 12 mutations / 10 6 bases) were also excluded from the analysis.
  • NFKBIZ colonic epithelial cells in which the function of NFKBIZ was deficient could not become cancerous, and even if they became cancerous, they could not proliferate, or both. This suggests that suppressing NFKBIZ has an effect of suppressing the development of cancer and an effect of suppressing the growth of the developed cancer.
  • Tumors developed were pathologically evaluated by HE staining and immunohistochemistry of ⁇ -catenin or Ki-67. For each mouse, body weight, colorectal length, and histological scores of enteritis were recorded. For histological scores of enteritis, epithelial damage and inflammatory cell infiltration were scored from 0 to 12 in five randomly selected high-power fields on the HE-stained slide (Goto, N. et al. Cancer Res 77: 3442 (2017)), the average of which was used in the analysis.
  • Maxwell manufactured by Promega
  • R Maxwell 16 LEV simplicity RNA Purification Kits
  • a real-time PCR reaction solution was prepared according to the protocol using the synthesized cDNA, human NFKBIZ or human ACTB gene-specific primer (manufactured by Origine), and iTaq Universal SYBR (R) Green Supermix (manufactured by Bio-Rad), and CFX384 (CFX384).
  • the reaction was carried out with Bio-Rad), and the reaction product was detected and quantified.
  • the value obtained by correcting the expression level of human NFKBIZ in each sample by the expression level of human ACTB was defined as the NFKBIZ expression level in each sample, and the value obtained by correcting the expression level of NFKBIZ in each sample by the expression level of NFKBIZ in the DMSO-added control sample was used. It was calculated as the relative mRNA expression level (NFKBIZ / ACTB) (FIG. 10).
  • the protein concentration was measured by BCA Protein Assay (manufactured by Thermo Fisher) and subjected to SDS-PAGE so as to be 20 ⁇ g per lane.
  • SDS-PAGE Any kD miniprotian TGX precast gel (Bio-Rad, 4569033) was used.
  • the expression of Legnes 1 was detected with an anti-Regnes 1 antibody (GTX110807, manufactured by GeneTex), and the expression of ⁇ -tubulin in the loading control was detected with an anti- ⁇ -tubulin antibody (2128S, manufactured by Cell Signaling Technology) (Fig. 11).
  • GS143 showed a strong cell growth inhibitory effect especially at a concentration of 10 ⁇ M or more. Since the concentration of 10 ⁇ M or more is the concentration at which the expression stabilization of legnes 1 and the accompanying suppression of NFKBIZ expression were observed in Examples 8 and 9, the E3 ligase inhibitor caused the expression of legnes 1. It has been found that by stabilizing and reducing the expression of NFKBIZ, it inhibits cell proliferation of colorectal cancer cell lines.
  • Example 7 Treatment example (1) Selection of patients The subject's cancer is diagnosed as being associated with chronic inflammation by colonoscopy, enema contrast examination, CT examination, MRI examination, or the like. The inflammatory state is measured by changes in the inflammatory parameters of the subject's blood and the extent and extent of inflammatory lesions in the cancerous tissue. (2) Formulation A preparation containing an NFKBIZ inhibitor and / or a Regnes 1 enhancer for treating a subject is provided. The drug is prepared as in GS143 (Example 7). (3) Treatment Considering the type of cancer of the subject, the degree of progression of the pathological condition, the suitability of GS143, the treatment history, the health condition, etc., GS143 is administered when the drug treatment is judged to be appropriate. (4) Results The therapeutic effect is evaluated by achieving the reduction or disappearance of the tumor of the subject and the alleviation of the inflammatory state by the administration of GS143.
  • Example 8 Therapeutic agent production GS143 is used as an NFKBIZ inhibitor and mixed with the following composition to prepare tablets for internal use.
  • Example 9 Examination of the role of NFKBIZ in enteritis (1) Method The following genetically modified C57BL / 6 mice were used. VilCremice (004586) and R26-LacZ mice (003309) were obtained from The Jackson Laboratory. Nfkbiz flox mice (Okuma, A. et al. Immunity 38: 450 (2013), RBRC06410) were obtained from the RIKEN BioResource Research Center. VilCre ER mice (el Marjou, F. et al. 39: 186 (2004)) were assigned by Sylvie Robine.
  • the NFKBIZ inhibitor according to the present invention is extremely useful for cancer associated with chronic inflammation.
  • the screening method of the present invention is useful for searching for an NFKBIZ inhibitor that is a candidate substance for a therapeutic or prophylactic drug for cancer.
  • SEQ ID NO: 1 shNFKBIZ 1 Target
  • SEQ ID NO: 2 shNFKBIZ 1
  • SEQ ID NO: 3 shNFKBIZ 2
  • Target SEQ ID NO: 4 shNFKBIZ 2
  • SEQ ID NO: 5 NFKBIZ Forward primer
  • SEQ ID NO: 6 NFKBIZ Reverse primer
  • SEQ ID NO: 7 18 Forward primer
  • SEQ ID NO: 8 18S rRNA Reverse primer

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Abstract

La présente invention concerne une composition pharmaceutique ou un procédé de traitement et/ou de prophylaxie du cancer, ou un procédé de criblage pour le criblage d'une substance ou d'un facteur pour le traitement et/ou la prophylaxie du cancer.　La présente invention concerne une composition pharmaceutique qui est destinée au traitement et/ou à la prophylaxie du cancer accompagné d'une inflammation chronique, et qui contient un inhibiteur de NFKBIZ. Des exemples d'inhibiteur de NFKBIZ comprennent des substances qui inhibent l'expression et/ou la fonction de NFKBIZ. Le cancer accompagné d'une inflammation chronique est de préférence un cancer associé à l'entérocolite observé dans la colite ulcéreuse.
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WO2023234297A1 (fr) * 2022-05-31 2023-12-07 国立大学法人京都大学 Composition pour le traitement du cancer

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