WO2011115246A1 - Inhibiteur de fonctionnalité de ebna1 - Google Patents

Inhibiteur de fonctionnalité de ebna1 Download PDF

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WO2011115246A1
WO2011115246A1 PCT/JP2011/056530 JP2011056530W WO2011115246A1 WO 2011115246 A1 WO2011115246 A1 WO 2011115246A1 JP 2011056530 W JP2011056530 W JP 2011056530W WO 2011115246 A1 WO2011115246 A1 WO 2011115246A1
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compound
ebna1
ebv
salt
virus
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PCT/JP2011/056530
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English (en)
Japanese (ja)
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耕司 野口
芳一 杉本
弘 杉山
俊和 板東
維文 簑島
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学校法人慶應義塾
国立大学法人京都大学
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Publication of WO2011115246A1 publication Critical patent/WO2011115246A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a compound useful as a function inhibitor of EBNA1 protein and its use.
  • EBV Epstein-Barr virus: human herpesvirus-4
  • latent infection the EBV genome becomes circular plasmid DNA (episome) and is stably maintained without being integrated into the genome of the infected cell, and in the lytic infection state, the linear EBV genome is replicated, incorporated into the virus particle, and released.
  • EBNA1 Epstein-Barr virus nuclear antigen 1
  • EBNA1 protein is a protein that plays an extremely important role in the replication and maintenance of EBV episomes in the latent state, as well as transcriptional expression of viral genes. If EBNA1 function is impaired, EBV episomal genomic DNA Cannot be maintained in infected cells, and the immortalization of B lymphocytes by EBV is also impaired.
  • antiviral drugs include biologics such as interferon, nucleic acid and non-nucleic acid inhibitors that target viral DNA and RNA polymerases, reverse transcription inhibitors known as anti-HIV drugs, protease inhibitors, Known are cell entry inhibitors, neuraminidase inhibitors known as anti-influenza drugs (WO 98/07685 pamphlet), and the like.
  • tumors caused by EBV are said to be related to latent infection, but inhibitors targeting EBNA1 protein, which has an important function during latent infection, are dominant negative mutants (Kennedy, G., Komano, J and Sugden.B. (2003) Proc. Natl. Acad. Sci. USA 100, 14269.
  • An object of the present invention is to provide a compound that inhibits the function of EBNA1 and its use, which are useful for the treatment or prevention of diseases caused by EB virus.
  • compound (1) a compound represented by the following formula (1) (hereinafter referred to as “compound (1)”) is an EBNA1 protein and viral genomic DNA. It has been found that it has an action of inhibiting the binding of EBNA1 protein, that is, an action of inhibiting the DNA binding ability of EBNA1 protein, and has completed the present invention.
  • the present invention is compound (1) or a salt thereof, or a hydrate or solvate thereof.
  • the pharmaceutical composition according to the present invention contains compound (1) or a salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • the EBNA1 function inhibitor according to the present invention contains compound (1) or a salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • the anti-EB virus (Epstein-Barr virus) drug according to the present invention contains compound (1) or a salt thereof, or a hydrate or solvate thereof.
  • the present invention is also the use of compound (1) or a salt thereof, or a hydrate or solvate thereof for producing an EBNA1 function inhibitor or an anti-EB virus agent.
  • the present invention is compound (1) or a salt thereof, or a hydrate or solvate thereof for inhibiting the function of EBNA1.
  • the present invention is Compound (1) or a salt thereof, or a hydrate or solvate thereof for preventing or treating EB virus infection.
  • the method according to the present invention is a method for inhibiting the function of EBNA1, and includes a step of allowing compound (1) or a salt thereof, or a hydrate or solvate thereof to act on EBNA1.
  • the present invention is a method for treating or preventing EB virus infection, comprising the step of administering compound (1) or a salt thereof, or a hydrate or solvate thereof.
  • the EBNA1 function inhibitor is, for example, an EBNA1 DNA binding inhibitor.
  • the function of EBNA1 is, for example, the DNA binding ability of EBNA1.
  • ⁇ acting '' refers to exerting an action of inhibiting the function of EBNA1 by adding or administering Compound (1) or a salt thereof, or a hydrate or solvate thereof, EBNA1 may be the target, or cultured cells that produce EBNA1 or cells in the individual may be the target.
  • the individual may be, for example, a human or a mammal other than that.
  • the anti-EB virus drug refers to a drug capable of treating or preventing a disease caused by EB virus using the function of EBNA1 protein as a molecular target.
  • the disease is, for example, a disease that develops when immunity is lowered in an EB virus latently infected mammal.
  • Examples of the EB virus infection include diseases that develop in EB virus latently infected mammals when immunity decreases.
  • Example of this invention it is the figure which showed typically the binding site of the compound (1) in the EBNA1 binding
  • the bold line attached to the base sequence at site 3 indicates the portion where compound (1) was expected to bind
  • the bold line attached to the base sequence at sites 1 and 4 represents compounds (1) and (2).
  • And (3) indicate the parts that are expected to be combined.
  • the bold line attached to the base sequence at site 3 indicates the portion where compound (1) was expected to bind
  • the bold line attached to the base sequence at sites 1 and 4 represents compounds (1) and (2).
  • And (3) indicate the parts that are expected to be combined.
  • compound (1) shows the results of EMSA in which binding of EBNA1 protein and EBV-producing strain Daudi or EB virus genomic DNA of B95-8 is inhibited.
  • the compound (1) that binds to EB virus genomic DNA in Daudi and other general cells and the EBNA1 protein substituted a partial base sequence of site 3 in the EB virus genomic DNA. It is a figure which shows not couple
  • it is a figure which shows the result of having investigated the toxicity of the compound (1) with respect to various cells.
  • it is a figure which shows the result of having investigated the growth inhibitory activity of compound (1), (4), and (6) with respect to B95-8 cell which is an EBV infection immortal cell.
  • EBV mainly infects B lymphocytes in the oropharyngeal region through saliva and the like, but is also known to infect oral mucosal epithelial cells. EBV latent infection is reported and widely recognized for its ability to transform human B lymphocytes into immortalized cells. In EBV-related human cancers, EBV is involved in malignant tumors such as Burkitt lymphoma, gastric cancer, nasopharyngeal cancer, NK / T cell lymphoma, and Hodgkin lymphoma. Clinically, EBV is recognized as a human cancer virus.
  • EBV infection occurs not in B lymphocytes but in T lymphocytes.
  • Chronic active EB virus infection a chronic lymphoproliferative disorder with fever, hepatoma, splenomegaly, or bone marrow EB virus-related hemophagocytic syndrome, in which hemophagocytosis is seen in lymph nodes, liver, etc., is known.
  • compound (1) has an action of inhibiting the function of EBNA1 protein as described above, compound (1) or a salt thereof, or a hydrate or solvate thereof is an EBNA1 protein function inhibitor, It is useful as an EB virus drug and the like, and is useful for a method for inhibiting EBNA1 function, a method for treating or preventing EB virus infection, and the like.
  • compound (1) or a salt thereof, or a hydrate or solvate thereof suppresses B cell immortalization by EBV, loss of EB virus genome itself from infected cells in a latent infection state, long-term EBV Decreased incidence of EBV-related malignant tumors due to latent infection, prevention of carcinogenesis due to EBV that cannot be excluded by so-called immune mechanism, suppression of virus growth from latently infected cells, suppression of EBV infection due to recurrent infection as a result of virus growth, etc. In particular, it works effectively on infected cells and tumor cells that cannot be excluded by the immune mechanism.
  • the function of the EBNA1 protein is, for example, the DNA binding ability of the EBNA1 protein.
  • diseases or EB virus infections for which the anti-EB virus drug of the present invention is useful include malignant tumors such as Burkitt lymphoma, gastric cancer, nasopharyngeal cancer, NK / T cell lymphoma, Hodgkin lymphoma, or malignant transformation thereof; Mononucleosis; EBV-related lymphoproliferative disorder (eg post-transplant lymphoproliferative disease or AIDS-related lymphoma) caused by abnormal immune status due to HIV infection, organ transplantation, malaria infection, etc .; chronic lymphoproliferative disease ( For example, chronic active EB virus infection etc.); EB virus related hemophagocytic syndrome etc. can be mentioned.
  • malignant tumors such as Burkitt lymphoma, gastric cancer, nasopharyngeal cancer, NK / T cell lymphoma, Hodgkin lymphoma, or malignant transformation thereof; Mononucleosis; EBV-related lymphoproliferative disorder
  • the above drugs may be administered as pharmaceuticals to mammals other than humans and non-humans (eg, mice, rats, dogs, cats, pigs, cows, horses, etc.), and may be used as experiments as reagents.
  • the drug may be in the form of tablets, capsules, granules, powders, syrups, injections, suppositories, liquids, sprays, sprays, coatings, sprays and the like.
  • These drugs may be in the form of solid, liquid, gel, powder, jelly, oil, paste, foam, cream or the like.
  • these drugs When these drugs are administered to mammals, they may be formulated and administered orally, or non-injected by intraperitoneal or intravenous injection or infusion, or sprayed or applied to the oropharyngeal region. It may be administered orally.
  • the preparation of the drug according to the present invention can be carried out by a conventional method using conventionally used preparation additives.
  • the formulation additive include existing additives such as excipients, binders, lubricants, disintegrants, flavoring agents, solvents, stabilizers, bases, wetting agents, preservatives, and the like. it can.
  • the above drugs are administered to treat or prevent malignant tumors such as Burkitt lymphoma, gastric cancer, nasopharyngeal cancer, NK / T cell lymphoma, Hodgkin lymphoma, or to prevent or suppress the malignant transformation of these malignant tumors
  • the anticancer agent may be added to the drug or may be administered separately.
  • alkylating drugs such as cyclophosphamide, antimetabolites such as cytarabine and methotrexate, and anticancer drugs such as rituximab, which is an anti-CD20 antibody, are added to the above drugs. It may be administered in combination with the above drugs.
  • prednisolone as a steroid, anticancer drug etoposide, immunosuppressive drug cyclosporine, etc. may be added to the drug. It may be administered separately.
  • the compound (1) according to the present invention can be produced by the method described below.
  • the salt of the compound represented by the compound (1), or the hydrate or solvate of the compound (1) or a salt thereof is usually used. Can be manufactured according to the law.
  • As the salt of compound (1) alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (magnesium salt, calcium salt, etc.), other metal salts (aluminum salt, etc.), inorganic salts (hydrochloride salt) , Ammonium salts, amines, etc.), organic salts (glucosamine salts, etc.) and the like.
  • a salt of compound (1) for the above-mentioned drug it is preferable to use a pharmacologically acceptable salt from the viewpoint of safety.
  • Example 1 Synthesis of Compounds (1) to (7) As shown in FIGS. 1 and 2, EBNA1 was predicted to interact in the OriP region of EBV genomic DNA, particularly in a region called dyad symmetry (DS).
  • DS dyad symmetry
  • the crudely purified compounds (1) to (7) were analyzed and purified by a high performance liquid chromatography apparatus (liquid feeding part; PU-2089, detector part; UV-2075, JASCO).
  • the stationary phase was a reverse phase column, chemcobond 5-ODS-H column (Chemco), and the detection wavelength was 254 nm.
  • As the mobile phase solvent a 0.1% acetic acid aqueous solution / acetonitrile mixed solution (acetic acid: Nacalai Tesque, acetonitrile: Kanto Chemical) was used. Further, the synthesis of the compounds (1) to (7) was confirmed by measuring the mass with a high performance quadrupole mass spectrometer API165E (Applied Biosystems).
  • Compound (1) C 56 H 73 N 23 O 11 ; calculated value 1244.6, actual value 1244.8; 25.8 mg (21 ⁇ mol) was obtained as a grey-brown powder.
  • Compound (2) C 60 H 75 N 23 O 11 ; calculated value 1294.6, measured value 1294.8; 22.0 mg (17 ⁇ mol) was obtained as a grey-brown powder.
  • Compound (3) C 60 H 75 N 23 O 11 ; calculated value 1294.6, measured value 1294.8; 11.7 mg (9.0 ⁇ mol) was obtained as a grayish brown powder.
  • Example 2 Experiments on inhibition of binding of EBNA1 protein and viral genomic DNA by each compound (1) It has been reported that a peptide consisting of the 461-607th amino acid sequence in the EBNA1 protein binds to viral genomic DNA (J. Mol. Biol. (1998), v284, p.1273-1278). Therefore, whether GST-EBNA1 (459-607) containing the above peptide and a fragment containing the DS region in OriP can be prepared, and can compounds (1)-(7) inhibit the binding of EBNA1 protein to viral genomic DNA? I checked.
  • This DNA fragment was ligated to pCR2.1 plasmid using TOPO TA cloning kit (Invitrogen) and then introduced into competent E. coli DH5alpha (Invitrogen). Extract the plasmid from Escherichia coli with the pCR2.1 plasmid inserted with EBNA1 (459-607) by alkaline extraction, and cut out the DNA fragment encoding EBNA1 (459-607) with the FLAG tag added by NcoI and EcoRI The gene was inserted into the NcoI-EcoRI site of the expression vector pET42c (Novagen) and introduced into competent E. coli Rosetta2 TM (DE3) pLysS strain (Novagen). After culturing E.
  • Glutathione Sepharose 4 Fast Flow (manufactured by GE Healthcare) was added to the supernatant, and Glutathione Sepharose 4 Fast Flow particles adsorbed with GST-EBNA1 (459-607) were collected in a pellet. This was washed with the above lysate, suspended in eluate (20 mM Glutathione (manufactured by SIGMA-ALDRICH), 50 mM Tris-Cl pH 8.5, 400 mM NaCl), and the supernatant was suspended in GST-EBNA1 (459- 607) It was recovered as a protein solution.
  • GST-EBNA1 protein was added to a final concentration of 20 nM, and the reaction was performed at room temperature for 1 hour. After the reaction, the reaction solution is removed from the well, washed 3 times with PBS solution, and 1% BSA-PBS containing 1 ⁇ g / ml Anti-FLAG M2 antibody-Peroxidase conjugated (manufactured by SIGMA-ALDRICH) is added to each well. It was allowed to react with the FLAG tag added to EBNA1 for 1 hour at room temperature.
  • Example 3 Experiment on inhibition of binding of EBNA1 protein and viral genomic DNA by each compound (2) Next, whether or not the compounds (1) to (7) can inhibit the binding between the EBNA1 protein and the viral genomic DNA was examined by EMSA (electrophoretic mobility shift assay). Final concentration 20 mM Tris-Cl pH 7.5, 150 mM NaCl, 2.5% glycerol, 5 mM MgCl 2 , 1 ⁇ g poly d (IC) (GE) in a 1.5 mL plastic tube to a final volume of 20 ⁇ L Healthcare), 50 fmole Biotin-OriP DNA fragment (used as a probe), 0-3 ⁇ M compounds (1) to (7), etc.
  • Example 4 Inhibition experiment of binding of EBNA1 protein and viral genomic DNA by compound (1)
  • compound (1) is a combination of EB viral genomic DNA and EBNA-1 in general cells other than B95-8. Whether the binding could be inhibited was examined by the same method as in Example 3.
  • the probe used was Biotin-OriP DNA fragment prepared in the same manner as described in Example 2-1, after extracting viral genomic DNA from Daudi cells (from Human Science Research Resource Bank). The result is shown in FIG.
  • Compound (1) not only binds EB virus genomic DNA and EBNA-1 in B95-8, but also binds EB virus genomic DNA and EBNA-1 in Daudi in a concentration-dependent manner. Inhibited. Again, a signal by supershift is detected by the binding of the complex of EBNA1 protein and viral genomic DNA to the compound, indicating that compound (1) is bound to the complex.
  • Example 5 In order to examine whether compound (1) and EBNA1 bind to site 3 of EB virus genomic DNA in general cells, the base sequence of a part of site 3 of EB virus genomic DNA derived from Daudi is determined. It was confirmed according to the method described in Example 3 whether the compound (1) and EBNA1 were bound using the substituted mutant.
  • the wild-type probe is a double-stranded DNA probe consisting of the following Site3 Fw probe and Site3 Rev probe
  • the mutant probe is a double-stranded DNA consisting of the following Mutant Site3 Fw probe and Mutant Site3 Rev probe. A probe was used. The result is shown in FIG. As shown in FIG.
  • Cytotoxicity test of compound (1) (MTT assay) Cells are seeded at 10,000 cells / well, and compound (1) is added to a final concentration of 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0 ⁇ M, and 5% CO at 37 ° C. The culture was performed for 5 days under the conditions of 2 . To measure viable cells, a solution of MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide; manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in PBS was used at a final concentration of 250 ⁇ g. to a total volume of 150 ⁇ L / well and further cultured for 4 hours.
  • MTT 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide
  • the cells include EBV-negative cells, K562 derived from human chronic myeloid leukemia, DG75 derived from human B lymphoma, and RamosRA1 derived from Burkitt lymphoma, and Raji, Daudi, and Namalwa derived from Burkitt lymphoma that are EBV positive cells. Using.
  • Example 7 Growth inhibition test of each compound against EBV-infected cells (crystal violet assay) It is a different type from the EBV positive cells used in Example 6, and the latent infection type of EBV is type III, and B95-8 cells expressing various viral genes contributing to cell immortalization are seeded at 1,000 cells / well. Compounds (1), (4), and (6) were added to final concentrations of 100, 50, 25, 12.5, 6.25, and 0 ⁇ M, and cultured at 37 ° C. under 5% CO 2 for 5 days. .
  • B95-8 cells were cultured using a culture solution of RPMI1640 (SIGM-ALDRICH) containing 7% FBS (fetal bovine serum) and 50 ⁇ g / ml kanamycin.
  • RPMI1640 SIGM-ALDRICH
  • FBS fetal bovine serum
  • compounds (1) and (6) have an inhibitory effect on the growth of EBV-infected B95-8 cells, and compound (1) is 64 ⁇ M which shows no toxicity in EBV-negative cells. It exhibits growth inhibitory activity that reduces the cell growth rate of B95-8 cells to 50% or less, and compound (6) also exhibits B95-8 cell growth inhibitory activity comparable to that of compound (1).
  • B95-8 cells are immortalized by EBV infection but are non-cancer cell lines whose growth depends on the expression of viral genes.
  • B95-8 cells are a cell line corresponding to cells in a latently infected state of EBV that cause EBV infection, and compounds (1) and (6) having an inhibitory effect on the growth of these cells are EBV-related lymphoproliferative diseases. It is useful for the treatment, prevention or suppression of the aforementioned EB virus infections such as post-transplant lymphoproliferative disease and AIDS-related lymphoma.

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Abstract

La présente invention concerne un inhibiteur de fonctionnalité de EBNA1 où un composé de formule (1), l'un de ses sels ou un hydrate ou solvate de ce composé ou sel exerce une action inhibitrice sur la liaison des protéines EBNA1 et de l'ADN génomique du virus. En d'autres termes, le composé, son sel ou un hydrate ou solvate dudit composé ou sel présente un effet inhibiteur sur la capacité à lier l'ADN des protéines EBNA1, et peu donc être employé en tant qu'inhibiteur de la fonctionnalité des protéines EBNA1.
PCT/JP2011/056530 2010-03-19 2011-03-18 Inhibiteur de fonctionnalité de ebna1 WO2011115246A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN109912577A (zh) * 2017-12-12 2019-06-21 深圳先进技术研究院 用于抑制eb病毒相关肿瘤的化合物及其制备方法和用途
WO2023200009A1 (fr) * 2022-04-15 2023-10-19 国立大学法人 東京大学 Inhibiteur du facteur de transcription protozoaire

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FRAPPIER L ET AL.: "Overproduction, purification, and characterization of EBNA1, the origin binding protein of Epstein-Barr virus", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 266, no. 12, 1991, pages 7819 - 7826 *
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109912577A (zh) * 2017-12-12 2019-06-21 深圳先进技术研究院 用于抑制eb病毒相关肿瘤的化合物及其制备方法和用途
CN109912577B (zh) * 2017-12-12 2021-10-22 深圳先进技术研究院 用于抑制eb病毒相关肿瘤的化合物及其制备方法和用途
WO2023200009A1 (fr) * 2022-04-15 2023-10-19 国立大学法人 東京大学 Inhibiteur du facteur de transcription protozoaire

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