WO2019111792A1 - GTP SENSOR PROTEIN PI5P4Kβ INHIBITOR - Google Patents

GTP SENSOR PROTEIN PI5P4Kβ INHIBITOR Download PDF

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WO2019111792A1
WO2019111792A1 PCT/JP2018/043919 JP2018043919W WO2019111792A1 WO 2019111792 A1 WO2019111792 A1 WO 2019111792A1 JP 2018043919 W JP2018043919 W JP 2018043919W WO 2019111792 A1 WO2019111792 A1 WO 2019111792A1
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pi5p4kβ
compound
inhibitor
gtp
compounds
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French (fr)
Japanese (ja)
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恒 竹内
俊哉 千田
敦朗 佐々木
快文 福西
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国立研究開発法人産業技術総合研究所
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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

Definitions

  • the present invention relates to inhibitors of PI5P4K ⁇ .
  • the present invention relates to an inhibitor that inhibits the function of PI5P4K ⁇ as a GTP sensor.
  • cancer is the leading cause of human death. About 50% of all these cancers are associated with mutations in the p53 gene. And such cancer with mutation of p53 gene is seen to acquire drug resistance and promote metastasis, and it is known that its prognosis is bad.
  • PI5P4K ⁇ phosphatidylinositol-5-phosphate-4-kinase ⁇
  • PI5P4K ⁇ Several compounds that inhibit the function of PI5P4K ⁇ have already been proposed (eg, non-patent documents 1 to 3). However, the IC50 values of these compounds are relatively large at several ⁇ M. Therefore, there is still a need for compounds that strongly inhibit PI5P4K ⁇ with lower IC50 values. These compounds can also act on homologues of PI5P4K ⁇ (in humans, PI5P4K ⁇ and PI5P4K ⁇ ). In particular, PI5P4K ⁇ has higher enzymological activity than PI5P4K ⁇ , and it is also important not to inhibit PI5P4K ⁇ , since PI5P4K ⁇ and PI5P4K ⁇ double knockout mice are lethal to many.
  • PI5P4K ⁇ compounds in which the IC50 value for PI5P4K ⁇ is sufficiently larger than the IC50 value for PI5P4K ⁇ are preferable. Since PI5P4K ⁇ has low activity, even if it is inhibited, its effect is limited and it is considered that it does not cause any problem.
  • An object of the present invention is to provide a PI5P4K ⁇ inhibitor that has a smaller IC50 value than conventional and can strongly inhibit PI5P4K ⁇ .
  • the present inventors focused on the extremely high intracellular GTP concentration of cancer cells, and by using a unique approach combining proteomics, biochemistry, structural biology and cell biological methods, PI5P4K ⁇ in mammalian cells
  • PI5P4K ⁇ functions as a sensor that detects and responds to GTP concentrations
  • the GTP sensor function of PI5P4K ⁇ promotes tumorigenesis. This is considered to be proof that p53 mutant cancer is dependent on GTP concentration sensing function.
  • the present invention is selected from the group consisting of compounds represented by the following structural formulas (1) to (4), pharmaceutically acceptable salts of these compounds, and pharmaceutically acceptable solvates thereof.
  • PI5P4K ⁇ inhibitors containing at least one of them as an active ingredient.
  • the present invention is also a method for inhibiting the function of PI5P4K ⁇ as a GTP sensor using the above-mentioned inhibitor.
  • the present invention is also a reagent composition for analysis of a GTP sensor mechanism involving PI5P4K ⁇ , which contains the above-mentioned inhibitor as an active ingredient.
  • the present invention is also an antitumor agent composition comprising the above-mentioned inhibitor as an active ingredient.
  • the present invention is also a method for preventing or treating tumor development, growth and / or malignancy by utilizing the above-mentioned method or administering the above-mentioned antitumor agent composition.
  • the present invention is a pharmaceutical composition for preventing or treating a disease relating to PI5P4K ⁇ hyperfunction, which comprises the above-mentioned inhibitor as an active ingredient.
  • All of the compounds of the present invention are capable of strongly inhibiting PI5P4K ⁇ with extremely low IC 50 values of less than 1 ⁇ M. Therefore, it is possible to provide a reagent for analysis of the function of PI5P4K ⁇ , a highly potent antitumor agent and an antitumor treatment.
  • the compounds of the present invention are also capable of strongly inhibiting PI5P4K ⁇ as compared to PI5P4K ⁇ . Therefore, it is possible to provide an antitumor agent and an antitumor treatment with high drug efficacy and few side effects. Furthermore, it is possible to provide a preventive or a remedy for diseases involving not only tumors and cancers but also PI5P4K ⁇ .
  • FIG. 1 It is a schematic diagram showing the outline of the screening. It is a measurement result of the IC50 value with respect to PI5P4K (beta) of a certain compound.
  • A It is a figure showing a mode that a compound (i) tautomerizes in water.
  • B) represents a compound (4) which is a stabilized compound of the compound (i). It is a result of the crystal structure analysis of the state which 2 types of compounds selected by the screening have couple
  • PI5P4K ⁇ is an enzyme (kinase) that phosphorylates the substrate phosphatidylinositol-5-phosphate. GTP is consumed in this phosphorylation. Although hypothesized, PI5P4K ⁇ functions as a GTP sensor that detects intracellular GTP concentration. More specifically, PI5P4K ⁇ detects intracellular GTP concentration, and consumes GTP to phosphorylate the substrate when GTP concentration is high. The phosphorylated substrate acts as a second messenger and eventually the cells become tumors. Therefore, if the function of PI5P4K ⁇ as a GTP sensor is inhibited, prevention of tumorigenesis of cells can be expected.
  • kinase kinase
  • the present inventors to verify this, to produce a mutant enzyme PI5P4K ⁇ F205L that have lost sensitivity to GTP. Growth on soft agar plates of cells expressing this mutant enzyme was significantly suppressed as compared to cells expressing wild type PI5P4K ⁇ . Furthermore, when cells expressing wild type PI5P4K ⁇ were transplanted to nude mice, half were engrafted and tumors were formed, whereas cells expressing the GTP independent PI5P4K ⁇ F205L mutant were transplanted to nude mice. Even no tumors formed.
  • the PI5P4K ⁇ inhibitor of the present invention is a group consisting of compounds represented by the following structural formulas (1) to (4), pharmaceutically acceptable salts of these compounds, and pharmaceutically acceptable solvates thereof. At least one selected from the above is contained as an active ingredient.
  • the compounds represented by Structural Formulas (1) to (4) may be expressed as Compound (1), Compound (2), Compound (3) and Compound (4), respectively.
  • the compound represented by Structural Formula (X) may be expressed as Compound (X).
  • “Contained as an active ingredient” means that PI5P4K ⁇ can be inhibited to a certain extent at a predetermined dose of the inhibitor.
  • the inhibitors of the present invention can be used either in vivo or in vitro. When in vivo, it may be administered to either unicellular or multicellular organisms. Multicellular organisms include fish, amphibians, reptiles, birds, mammals other than humans, and humans, which may be administered to any of them. When in vitro, it may be administered to cells, cells derived from multicellular organisms, or cell tissues derived from multicellular organisms.
  • the compounds represented by structural formulas (1) to (4) include all tautomers, geometric isomers and stereoisomers such as enantiomers which can be present, unless otherwise specified.
  • the method for obtaining the compounds represented by structural formulas (1) to (4) is optional, and may be synthesized by itself or may be obtained commercially.
  • the synthesis method of the compounds represented by structural formulas (1) to (4) is not particularly limited, and various known methods may be synthesized alone or in combination.
  • the compound represented by the structural formula (1) (CAS No. 19795-96-1, PubChem No. 88253) is commercially available, for example, from Vitas-M under the trade name “STK238453”.
  • the compound represented by the structural formula (2) can be obtained commercially, for example, from TimTec under the trade name “ST095461”.
  • the compound represented by the structural formula (3) (CAS No. 13710-19-5, PubChem No. 610479) can be commercially obtained, for example, from Sigma Co., Ltd. under the trade name “tolfenic acid”.
  • the compound represented by structural formula (4) is commercially available, for example, from Labotest under the trade name “LT00097173”.
  • pharmaceutically acceptable means generally not harmful to the recipient at the dose to achieve the desired main effect.
  • alkali metal salts such as lithium salts, sodium salts and potassium salts
  • alkaline earth metal salts such as magnesium salts and calcium salts.
  • basic amino acid addition salts such as lysine, ⁇ -hydroxylysine, arginine and the like can be mentioned.
  • the pharmaceutically acceptable salt when the compound has a basic group, the following may be mentioned.
  • mineral acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates and phosphates; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionate, tartaric acid, fumaric acid, maleic acid
  • the acid include malic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, and organic acid salts such as salicylic acid.
  • acidic amino acid addition salts such as aspartic acid and glutamic acid can be mentioned.
  • pharmaceutically acceptable solvates include, for example, hydrate, alcoholate, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, chloroform, dichloroethane, dichloromethane, diethyl ether Methyl t-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, isobutyl methyl ketone, toluene, benzene, o-xylene, m -Xylene, p-xylene, ethyl acetate, propyl acetate, butyl acetate, propylene carbonate, diethyl carbonate, dimethyl carbonate, hexane, Tan, h
  • solvates with pharmaceutically acceptable solvents selected from the group consisting of octane and cyclohexane. Among these, hydrates are usually preferred. Here, the solvate with the solvent which was used when synthesize
  • the IC 50 values for PI5P4K ⁇ of the compounds represented by structural formulas (1) to (4) are extremely small, less than 1 ⁇ M. It is speculated that administration of a small amount of these compounds sufficiently inhibits PI5P4K ⁇ . Therefore, it is considered possible to inhibit the function of PI5P4K ⁇ (in particular, the function as a GTPase and / or the function as a GTP sensor) by administration of compounds represented by structural formulas (1) to (4).
  • these compounds are advantageous in that they exert stronger action on PI5P4K ⁇ than PI5P4K ⁇ .
  • the IC50 values for PI5P4K ⁇ , a family of PI5P4K ⁇ are 200 ⁇ M or more for compound (1), 20 ⁇ M or more for compound (2), 100 ⁇ M or more for compound (3), and 40 ⁇ M or more for compound (4) is there. It was confirmed that PI5P4K ⁇ and PI5P4K ⁇ act extremely selectively on PI5P4K ⁇ because all compounds have an IC50 value of less than 1 ⁇ M against PI5P4K ⁇ .
  • an IC50 value means the density
  • PI5P4K ⁇ functions as a GTP sensor.
  • the PI5P4K ⁇ inhibitor of the present invention can be used as an active ingredient of a reagent for analysis of GTP sensor mechanism involving PI5P4K ⁇ .
  • the analysis reagent of the present invention contains the above-mentioned PI5P4K ⁇ inhibitor as an active ingredient. Other than this inhibitor, any component may be included.
  • PI5P4K ⁇ is an important factor in tumorigenesis.
  • the functional inhibition of PI5P4K ⁇ in turn includes the prevention (both complete prevention and delay) of tumorigenesis or carcinogenesis (malignancy of tumor) of p53 gene mutant cells, p53 gene mutant cells, p53 gene mutant cells It is speculated that it will lead to the prevention of tumor or cancer growth (meaning both complete arrest and slowing down) or treatment of p53 gene mutated tumor or cancer (meaning both cure and alleviation). Therefore, the PI5P4K ⁇ inhibitor of the present invention can be used as an active ingredient of an antitumor agent.
  • the antitumor agent of the present invention contains the PI5P4K ⁇ inhibitor described above as an active ingredient.
  • any component may be included as long as it is pharmaceutically acceptable.
  • containing as an active ingredient means that a PI5P4K ⁇ inhibitor can be administered in an amount such that a desired effect can be obtained at a predetermined dose of an analysis reagent or an antitumor agent.
  • the dose of the inhibitor of the present invention is 0.001 mg or more, 0.01 mg or more, and 0.1 mg or more per kg of body weight per day and when it is administered to an organism as an antitumor agent, although it is a guide to the last.
  • the content in the drug is preferably determined to be 0.5 mg or more or 1 mg or more.
  • the dose of the inhibitor of the present invention is 100 mg or less, 10 mg or less, 9 mg or less, 8 mg or less, 7 mg or less, 6 mg or less, 5 mg or less, 4 mg or less per day and per kg body weight
  • the content in the drug is determined to be 3 mg or less.
  • the content of the PI5P4K ⁇ inhibitor in the analysis reagent or the antitumor agent is usually 1 to 90% by mass, based on the total amount of the analysis reagent or the total amount of the antitumor agent. 2 mass% or more, 3 mass% or more, 4 mass% or more, 5 mass% or more, 6 mass% or more, 7 mass% or more, 8 mass% or more, 9 mass% or more, 10 mass% or more, 15 mass% or more, It is good also as 20 mass% or more, 25 mass% or more, and 30 mass% or more. On the other hand, 85% by mass, 80% by mass, 75% by mass, 70% by mass, 65% by mass, 60% by mass, 55% by mass, 50% by mass, 45% by mass or less.
  • the antitumor agent of the present invention is a microtubule assembly inhibitor, AKT inhibitor, mTOR inhibitor, MEK inhibitor, RTK inhibitor, ATM inhibitor, ATR inhibitor, PI3K inhibitor, EGFR inhibitor, B-Raf inhibition It may further contain one or more agents selected from the group consisting of agents, C-kit inhibitors, PARP inhibitors, DNA crosslinkers, DNA intercalators, and cytidine analogs.
  • the antitumor agent of the present invention can optionally contain pharmaceutically acceptable additives such as coloring agents, preservatives, flavors, flavors, sweeteners and other therapeutic agents.
  • Such stabilizers include, for example, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like.
  • the antitumor agent of the present invention may further contain, as an optional component, any pharmaceutically acceptable diluent, carrier, excipient and the like.
  • the subject to which the antitumor agent of the present invention is to be applied is not particularly limited as long as it is a tumor containing a mutant cell with a p53 gene mutation (preferably, one that shows an improvement in the activity of PI5P4K ⁇ ).
  • the tumor may be a malignant tumor (cancer).
  • tumors and cancers examples include colon cancer, colorectal cancer, stomach cancer, lung cancer, pancreatic cancer, prostate cancer, kidney cancer, thyroid cancer, breast cancer, biliary cancer, leukemia, brain cancer, Lymphoma, osteosarcoma, myeloma, brain tumor and the like.
  • the antitumor agent of the present invention can be formulated into any dosage form.
  • the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, injections and the like.
  • the antitumor agent of the present invention may be administered by any method such as oral administration, intraperitoneal administration, intradermal administration, intravenous administration, intramuscular administration, intracerebral administration and the like.
  • the dose of the antitumor agent of the present invention is appropriately adjusted according to the condition, age, sex, components of the antitumor agent, and the like of the subject of administration.
  • the PI5P4K ⁇ inhibitor of the present invention can be used for diseases caused or exacerbated by enhancement of the function of PI5P4K ⁇ (in particular, the function as a GTP sensor and / or the function as a GTPase) other than tumors and cancers.
  • diseases include diabetes. Therefore, the inhibitor of the present invention can be used as an active ingredient of a preventive or therapeutic agent for metabolic diseases such as diabetes.
  • PI5P4K ⁇ inhibitory compounds were searched according to the method disclosed in Japanese Patent Application Laid-Open No. 2017-040603 (name of the invention “Method for screening a drug using NMR”).
  • the compounds targeted are the Pharmakon-1600 compound 1600 and the MSM-MTS method (Fukunishi, Y. Mikami, S. Kubota, H. Nakamura, “Multiple target screening method for accurate and accurate in silico screening.” Journal of Molecular Graphics and Modeling, 25, 61-70 (2005); Y. Fukunishi, S. Kubota, H.
  • a reaction solution a reaction solution in which 250 ⁇ M of GTP, 1.5 ⁇ M of PI5P4K ⁇ were dissolved in 10 mM of Phosphate (pH 7.5), 100 mM of NaCl, and 10 mM of MgCl 2 was prepared. 25 ⁇ L of the compound solution and 500 ⁇ L of the reaction solution were mixed, and reacted at 25 ° C. for 20 hours. The DMSO concentration in each sample was adjusted to 5%.
  • the IC50 value of compound (i) is 1.4 ⁇ M
  • the IC50 value of compound (3) is 0.57 ⁇ M
  • the IC50 value of compound (a) is 4.
  • the concentration was 7 ⁇ M, and it became clear that the compound (i) and the compound (3) exhibited stronger inhibitory activity than the conventionally known PI5P4K ⁇ inhibitor compound (a) (FIG. 2).
  • the IC50 value of PI5P4K ⁇ inhibitor compound SAR088 (a compound represented by the following structural formula (b), hereinafter also referred to as compound (b)) described in Non-patent document 2 presented in the present application is described as 3.8 ⁇ M Better than this. That is, it became clear that the compound (i) and the compound (3) show higher inhibitory activity than the conventional PI5P4K ⁇ inhibitory compound.
  • Compound (1) and Compound (2) already reduced the activity of PI5P4K ⁇ to less than 10% and less than 40%, respectively, at 0.5 ⁇ M which is the lowest concentration at which the activity can be evaluated by NMR. That is, its IC50 value is less than 0.5 ⁇ M.
  • each of the compounds (1) to (4) is a compound that binds to the GTP site of PI5P4K ⁇ , and is a compound capable of inhibiting the function of PI5P4K ⁇ as the GTPase and / or the function as the GTP sensor I understand. Also, its IC50 value shows significantly stronger inhibitory activity than the conventional inhibitory compounds, less than 1 ⁇ M (FIG. 5). Functional inhibition of PI5P4K ⁇ by these compounds is useful for analysis of GTP sensor mechanism. It is also expected to exert anti-tumor activity through the inhibition of the GTP sensor PI5P4K ⁇ .
  • these compounds can be used for prevention and treatment of diseases caused and / or deteriorated by enhancement of the function of PI5P4K ⁇ .
  • these compounds are advantageous in that the IC50 value against PI5P4K ⁇ is small, while the IC50 value against PI5P4K ⁇ is sufficiently large compared to the IC50 value against PI5P4K ⁇ , and inhibition of PI5P4K ⁇ is less likely to occur.

Abstract

[Problem] To provide a PI5P4Kβ inhibitor having a lower IC50 than conventional inhibitors and capable of strongly inhibiting PI5P4Kβ. [Solution] A PI5P4Kβ inhibitor containing, as an effective component, at least one selected from the group consisting of compounds represented by structural formulas (1) to (4), pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof.

Description

ＧＴＰセンサータンパク質ＰＩ５Ｐ４Ｋβの阻害剤Inhibitor of GTP sensor protein PI5P4Kβ
　本発明は、ＰＩ５Ｐ４Ｋβの阻害剤に関する。特にＰＩ５Ｐ４ＫβのＧＴＰセンサーとしての機能を阻害する阻害剤に関する。 The present invention relates to inhibitors of PI5P4Kβ. In particular, the present invention relates to an inhibitor that inhibits the function of PI5P4Kβ as a GTP sensor.
　がんが人間の死因の上位を占めていることは周知の事実である。これらがん全体のうち約５０％がｐ５３遺伝子の変異を伴っている。そしてｐ５３遺伝子の変異を伴うこのようながんは、薬剤耐性の獲得や転移の促進が見られ、その予後が悪いことが知られている。 It is a well-known fact that cancer is the leading cause of human death. About 50% of all these cancers are associated with mutations in the p53 gene. And such cancer with mutation of p53 gene is seen to acquire drug resistance and promote metastasis, and it is known that its prognosis is bad.
　近年、ｐ５３変異がんの腫瘍形成に重要な因子として、イノシトールリン脂質キナーゼの一種ホスファチジルイノシトール－５－リン酸－４－キナーゼβ（ＰＩ５Ｐ４Ｋβ）が同定された。そのため、このＰＩ５Ｐ４Ｋβの機能を阻害し抗腫瘍剤として利用し得る化合物の同定・開発が行われている。 In recent years, phosphatidylinositol-5-phosphate-4-kinase β (PI5P4Kβ), which is a type of inositol phospholipid kinase, has been identified as an important factor for tumorigenesis of p53 mutant cancer. Therefore, identification and development of compounds that can inhibit the function of PI5P4Kβ and can be used as an antitumor agent have been conducted.
　ＰＩ５Ｐ４Ｋβの機能を阻害する化合物が幾つか既に提案されている（例えば、非特許文献１～３）。しかしながらこれら化合物のIC50値は数μＭと比較的大きい。そのため、より小さいIC50値でＰＩ５Ｐ４Ｋβを強く阻害する化合物が依然として求められている。またこれら化合物はＰＩ５Ｐ４Ｋβのホモログ（ヒトにおいてはＰＩ５Ｐ４ＫαとＰＩ５Ｐ４Ｋγ）にも作用し得る。特にＰＩ５Ｐ４ＫαはＰＩ５Ｐ４Ｋβよりも酵素学的活性が高く、ＰＩ５Ｐ４ＫαとＰＩ５Ｐ４Ｋβのダブルノックアウトマウスは大勢致死となるため、ＰＩ５Ｐ４Ｋαを阻害しないことも重要である。そのため、ＰＩ５Ｐ４Ｋαに対するIC50値が、ＰＩ５Ｐ４Ｋβに対するIC50値よりも十分大きい化合物が好ましい。なお、ＰＩ５Ｐ４Ｋγはその活性が低いことから、仮に阻害を行ってもその効果は限定的であり、問題にならないと考えられる。 Several compounds that inhibit the function of PI5P4Kβ have already been proposed (eg, non-patent documents 1 to 3). However, the IC50 values of these compounds are relatively large at several μM. Therefore, there is still a need for compounds that strongly inhibit PI5P4Kβ with lower IC50 values. These compounds can also act on homologues of PI5P4Kβ (in humans, PI5P4Kα and PI5P4Kγ). In particular, PI5P4Kα has higher enzymological activity than PI5P4Kβ, and it is also important not to inhibit PI5P4Kα, since PI5P4Kα and PI5P4Kβ double knockout mice are lethal to many. Therefore, compounds in which the IC50 value for PI5P4Kα is sufficiently larger than the IC50 value for PI5P4Kβ are preferable. Since PI5P4Kγ has low activity, even if it is inhibited, its effect is limited and it is considered that it does not cause any problem.
　本発明は、従来よりもIC50値が小さく、ＰＩ５Ｐ４Ｋβを強く阻害することができるＰＩ５Ｐ４Ｋβ阻害剤を提供することを目的とする。 An object of the present invention is to provide a PI5P4Kβ inhibitor that has a smaller IC50 value than conventional and can strongly inhibit PI5P4Kβ.
　本発明者らは前記課題について鋭意研究した結果、本発明を完成するに至った。 As a result of intensive studies on the above-mentioned problems, the present inventors have completed the present invention.
　まず本発明者らは、がん細胞の細胞内ＧＴＰ濃度が著しく高いことに着目し、プロテオミクス、生化学、構造生物学および細胞生物学的手法を組み合わせた独自のアプローチにより、ＰＩ５Ｐ４Ｋβが哺乳細胞においてＧＴＰ濃度を検知・応答するセンサーとして機能すること、そしてＰＩ５Ｐ４ＫβのＧＴＰセンサー機能が腫瘍形成を促進することを発見した。このことは、ｐ５３変異がんがＧＴＰ濃度感知機能に依存していることの証左と考えられる。これらの知見に基づき、ＰＩ５Ｐ４ＫβをＧＴＰセンサーとして位置付け、ＰＩ５Ｐ４Ｋβを小さいIC50値で強く阻害する化合物の同定を試み、所定の化合物がＰＩ５Ｐ４Ｋβ阻害剤として使用できることを見出した。 First of all, the present inventors focused on the extremely high intracellular GTP concentration of cancer cells, and by using a unique approach combining proteomics, biochemistry, structural biology and cell biological methods, PI5P4Kβ in mammalian cells We have found that it functions as a sensor that detects and responds to GTP concentrations, and that the GTP sensor function of PI5P4Kβ promotes tumorigenesis. This is considered to be proof that p53 mutant cancer is dependent on GTP concentration sensing function. Based on these findings, we have positioned PI5P4Kβ as a GTP sensor and tried to identify a compound that strongly inhibits PI5P4Kβ with a small IC50 value, and found that a given compound can be used as a PI5P4Kβ inhibitor.
　すなわち本発明は、下記構造式（１）～（４）で表現される化合物およびこれら化合物の医薬的に許容される塩、並びにそれらの医薬的に許容される溶媒和物から成る群より選択される少なくとも１つを有効成分として含有するＰＩ５Ｐ４Ｋβ阻害剤である。
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-I000006
Figure JPOXMLDOC01-appb-I000007
Figure JPOXMLDOC01-appb-I000008
That is, the present invention is selected from the group consisting of compounds represented by the following structural formulas (1) to (4), pharmaceutically acceptable salts of these compounds, and pharmaceutically acceptable solvates thereof. PI5P4Kβ inhibitors containing at least one of them as an active ingredient.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-I000006
Figure JPOXMLDOC01-appb-I000007
Figure JPOXMLDOC01-appb-I000008
　また本発明は、上記の阻害剤を使用してＰＩ５Ｐ４ＫβのＧＴＰセンサーとしての機能を阻害する方法である。 The present invention is also a method for inhibiting the function of PI5P4Kβ as a GTP sensor using the above-mentioned inhibitor.
　また本発明は、上記の阻害剤を有効成分として含有する、ＰＩ５Ｐ４Ｋβが関与するＧＴＰセンサー機構の解析に用いられる試薬組成物である。 The present invention is also a reagent composition for analysis of a GTP sensor mechanism involving PI5P4Kβ, which contains the above-mentioned inhibitor as an active ingredient.
　また本発明は、上記の阻害剤を有効成分として含有する抗腫瘍剤組成物である。 The present invention is also an antitumor agent composition comprising the above-mentioned inhibitor as an active ingredient.
　また本発明は、上記の方法を利用して、または上記の抗腫瘍剤組成物を投与して、腫瘍の発生、増殖および／または悪性化を予防ないし治療する方法である。 The present invention is also a method for preventing or treating tumor development, growth and / or malignancy by utilizing the above-mentioned method or administering the above-mentioned antitumor agent composition.
　さらに本発明は、上記の阻害剤を有効成分として含有する、ＰＩ５Ｐ４Ｋβの機能亢進に関する疾病を予防ないし治療するための医薬組成物である。 Furthermore, the present invention is a pharmaceutical composition for preventing or treating a disease relating to PI5P4Kβ hyperfunction, which comprises the above-mentioned inhibitor as an active ingredient.
　本発明に係る化合物はいずれも、１μＭ未満という極めて小さいIC50値でＰＩ５Ｐ４Ｋβを強く阻害することが可能である。そのためＰＩ５Ｐ４Ｋβの機能に関する解析用試薬、薬効が高い抗腫瘍剤および抗腫瘍治療を提供することができる。また本発明に係る化合物は、ＰＩ５Ｐ４Ｋαに比べてＰＩ５Ｐ４Ｋβを強く阻害することが可能である。そのため薬効が高く、且つ、副作用の少ない抗腫瘍剤および抗腫瘍治療を提供することができる。さらには腫瘍やがんだけでなく、ＰＩ５Ｐ４Ｋβが関与する疾病の予防薬や治療薬を提供することができる。 All of the compounds of the present invention are capable of strongly inhibiting PI5P4Kβ with extremely low IC 50 values of less than 1 μM. Therefore, it is possible to provide a reagent for analysis of the function of PI5P4Kβ, a highly potent antitumor agent and an antitumor treatment. The compounds of the present invention are also capable of strongly inhibiting PI5P4Kβ as compared to PI5P4Kα. Therefore, it is possible to provide an antitumor agent and an antitumor treatment with high drug efficacy and few side effects. Furthermore, it is possible to provide a preventive or a remedy for diseases involving not only tumors and cancers but also PI5P4Kβ.
スクリーニングの概略を現した模式図である。It is a schematic diagram showing the outline of the screening. ある化合物のＰＩ５Ｐ４Ｋβに対するIC50値の測定結果である。It is a measurement result of the IC50 value with respect to PI5P4K (beta) of a certain compound. （Ａ）化合物（ｉ）が水中で互変異性する様子を表す図である。　　　　　（Ｂ）化合物（ｉ）の安定化化合物である化合物（４）を表す。(A) It is a figure showing a mode that a compound (i) tautomerizes in water. (B) represents a compound (4) which is a stabilized compound of the compound (i). スクリーニングで選ばれた２種の化合物がＰＩ５Ｐ４Ｋβと結合している状態の結晶構造解析の結果である。It is a result of the crystal structure analysis of the state which 2 types of compounds selected by the screening have couple | bonded with PI5P4K (beta). 本発明に係る化合物と従来周知の化合物との対比である。It is a contrast with the compound based on this invention, and a conventionally well-known compound.
　以下、本発明について詳述する。 Hereinafter, the present invention will be described in detail.
　ＰＩ５Ｐ４Ｋβは基質であるホスファチジルイノシトール－５－リン酸をリン酸化する酵素（キナーゼ）である。このリン酸化においてＧＴＰを消費する。仮説ではあるが、ＰＩ５Ｐ４Ｋβは細胞内のＧＴＰ濃度を検知するＧＴＰセンサーとして機能する。より具体的には、ＰＩ５Ｐ４Ｋβが細胞内のＧＴＰ濃度を検知し、ＧＴＰ濃度が高い場合にはＧＴＰを消費して基質をリン酸化する。リン酸化された基質がセカンドメッセンジャーとして作用し、最終的に細胞が腫瘍となる。そのためＰＩ５Ｐ４ＫβのＧＴＰセンサーとしての機能を阻害すれば細胞の腫瘍化の予防などが期待できる。 PI5P4Kβ is an enzyme (kinase) that phosphorylates the substrate phosphatidylinositol-5-phosphate. GTP is consumed in this phosphorylation. Although hypothesized, PI5P4Kβ functions as a GTP sensor that detects intracellular GTP concentration. More specifically, PI5P4Kβ detects intracellular GTP concentration, and consumes GTP to phosphorylate the substrate when GTP concentration is high. The phosphorylated substrate acts as a second messenger and eventually the cells become tumors. Therefore, if the function of PI5P4Kβ as a GTP sensor is inhibited, prevention of tumorigenesis of cells can be expected.
  そこで、これを検証するために本発明者らは、ＧＴＰに対する感受性を喪失した変異体酵素ＰＩ５Ｐ４ＫβＦ２０５Ｌを作製した。この変異体酵素を発現させた細胞の軟寒天プレートにおける増殖は、野生型ＰＩ５Ｐ４Ｋβを発現させた細胞に比べ有意に抑制された。さらに、野生型ＰＩ５Ｐ４Ｋβを発現させた細胞をヌードマウスに移植したところ半数が生着し腫瘍を形成したのに対し、ＧＴＰ非依存的ＰＩ５Ｐ４ＫβＦ２０５Ｌ変異体を発現させた細胞はヌードマウスに移植しても腫瘍をまったく形成しなかった。このことから、ＰＩ５Ｐ４ＫβのＧＴＰセンサーは腫瘍の形成に寄与することが明らかにされた（Sumita, Lo, Takeuchi, et al., Molecular Cell, 61, 187-198 (2016) 特にFig.6参照）。 Accordingly, the present inventors to verify this, to produce a mutant enzyme PI5P4Kβ F205L that have lost sensitivity to GTP. Growth on soft agar plates of cells expressing this mutant enzyme was significantly suppressed as compared to cells expressing wild type PI5P4Kβ. Furthermore, when cells expressing wild type PI5P4Kβ were transplanted to nude mice, half were engrafted and tumors were formed, whereas cells expressing the GTP independent PI5P4Kβ F205L mutant were transplanted to nude mice. Even no tumors formed. From this, it was revealed that the GTP sensor of PI5P4Kβ contributes to the formation of a tumor (Sumita, Lo, Takeuchi, et al., Molecular Cell, 61, 187-198 (2016), particularly, see FIG. 6).
　本発明のＰＩ５Ｐ４Ｋβ阻害剤は、下記構造式（１）～（４）で表現される化合物およびこれら化合物の医薬的に許容される塩、並びにそれらの医薬的に許容される溶媒和物から成る群より選択される少なくとも１つを有効成分として含有する。
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-I000010
Figure JPOXMLDOC01-appb-I000011
Figure JPOXMLDOC01-appb-I000012
The PI5P4Kβ inhibitor of the present invention is a group consisting of compounds represented by the following structural formulas (1) to (4), pharmaceutically acceptable salts of these compounds, and pharmaceutically acceptable solvates thereof. At least one selected from the above is contained as an active ingredient.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-I000010
Figure JPOXMLDOC01-appb-I000011
Figure JPOXMLDOC01-appb-I000012
　以下、構造式（１）～（４）で表現される化合物のことを、それぞれ化合物（１）、化合物（２）、化合物（３）、化合物（４）と表現する場合もある。同様に、構造式（Ｘ）で表現される化合物を化合物（Ｘ）と表現することがある。 Hereinafter, the compounds represented by Structural Formulas (1) to (4) may be expressed as Compound (1), Compound (2), Compound (3) and Compound (4), respectively. Similarly, the compound represented by Structural Formula (X) may be expressed as Compound (X).
　『有効成分として含有する』とは、所定の阻害剤の投与量においてＰＩ５Ｐ４Ｋβを一定程度阻害できることを意味する。 “Contained as an active ingredient” means that PI5P4Kβ can be inhibited to a certain extent at a predetermined dose of the inhibitor.
　本発明の阻害剤は、in vivoとin vitroのいずれにおいても使用可能である。in vivoの場合、単細胞生物、多細胞生物のいずれに投与してもよい。多細胞生物としては魚類、両生類、爬虫類、鳥類、人類を除く哺乳類および人類が挙げられ、いずれに投与してもよい。in vitroの場合、細胞、多細胞生物由来細胞、多細胞生物由来細胞組織いずれに投与してもよい。 The inhibitors of the present invention can be used either in vivo or in vitro. When in vivo, it may be administered to either unicellular or multicellular organisms. Multicellular organisms include fish, amphibians, reptiles, birds, mammals other than humans, and humans, which may be administered to any of them. When in vitro, it may be administered to cells, cells derived from multicellular organisms, or cell tissues derived from multicellular organisms.
　構造式（１）～（４）で表現される化合物には、特に断らない限り、存在し得る互変異性体、幾何異性体、鏡像異性体などの立体異性体のいずれもが含まれる。 The compounds represented by structural formulas (1) to (4) include all tautomers, geometric isomers and stereoisomers such as enantiomers which can be present, unless otherwise specified.
　構造式（１）～（４）で表現される化合物の入手方法は任意であり、自ら合成してもよいし、商業的に入手してもよい。 The method for obtaining the compounds represented by structural formulas (1) to (4) is optional, and may be synthesized by itself or may be obtained commercially.
　構造式（１）～（４）で表現される化合物の合成方法は特に限定されず、従来公知の種々の方法を単独または組み合わせて合成すればよい。 The synthesis method of the compounds represented by structural formulas (1) to (4) is not particularly limited, and various known methods may be synthesized alone or in combination.
 　各化合物を商業的に入手する場合、例えば、以下の通り商業的に入手できる。 When each compound is obtained commercially, it is commercially available, for example, as follows.
　構造式（１）で表現される化合物（CAS番号19795-96-1、PubChem番号88253）は、例えば、Vitas-M社から、商品名「STK238453」として、商業的に入手することができる。 The compound represented by the structural formula (1) (CAS No. 19795-96-1, PubChem No. 88253) is commercially available, for example, from Vitas-M under the trade name “STK238453”.
　構造式（２）で表現される化合物は、例えば、TimTec社から、商品名「ST095461」として、商業的に入手することができる。 The compound represented by the structural formula (2) can be obtained commercially, for example, from TimTec under the trade name “ST095461”.
　構造式（３）で表現される化合物（CAS番号13710-19-5、PubChem番号610479）は、例えば、Sigma社などから、商品名「tolfenamic acid」として、商業的に入手することができる。 The compound represented by the structural formula (3) (CAS No. 13710-19-5, PubChem No. 610479) can be commercially obtained, for example, from Sigma Co., Ltd. under the trade name “tolfenic acid”.
　構造式（４）で表現される化合物は、例えば、Labotest社から、商品名「LT00097173」として、商業的に入手することができる。 The compound represented by structural formula (4) is commercially available, for example, from Labotest under the trade name “LT00097173”.
　本発明において、「医薬的に許容される」とは、所望の主作用を得るための投与量において投与対象者にとって通常、有害ではないことを意味する。 In the present invention, "pharmaceutically acceptable" means generally not harmful to the recipient at the dose to achieve the desired main effect.
　本発明において、医薬的に許容される塩としては、化合物が酸性基を有する場合には、以下のものが挙げられる。 In the present invention, as the pharmaceutically acceptable salt, when the compound has an acidic group, the following may be mentioned.
　例えば、リチウム塩、ナトリウム塩、カリウム塩などのアルカリ金属塩；マグネシウム塩、カルシウム塩などのアルカリ土類金属塩などが挙げられる。またリジン、δ－ヒドロキシリジン、アルギニンなどの塩基性アミノ酸付加塩などが挙げられる。さらにはアンモニア、メチルアミン、ジメチルアミン、トリメチルアミン、ジシクロヘキシルアミン、トリス（ヒドロキシメチル）アミノメタン、Ｎ，Ｎ－ビス（ヒドロキシエチル）ピペラジン、２－アミノ－２－メチル－１－プロパノール、エタノールアミン、Ｎ－メチルグルカミン、Ｌ－グルカミンなどのアミン付加塩などが挙げられる。 Examples thereof include alkali metal salts such as lithium salts, sodium salts and potassium salts; and alkaline earth metal salts such as magnesium salts and calcium salts. In addition, basic amino acid addition salts such as lysine, δ-hydroxylysine, arginine and the like can be mentioned. Furthermore, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N Amine addition salts such as methylglucamine, L-glucamine and the like.
　本発明において、医薬的に許容される塩としては、化合物が塩基性基を有する場合には、以下のものが挙げられる。 In the present invention, as the pharmaceutically acceptable salt, when the compound has a basic group, the following may be mentioned.
　例えば、塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩などの無機酸塩；メタンスルホン酸、ベンゼンスルホン酸、パラトルエンスルホン酸、酢酸、プロピオン酸塩、酒石酸、フマル酸、マレイン酸、リンゴ酸、シュウ酸、コハク酸、クエン酸、安息香酸、マンデル酸、ケイ皮酸、乳酸、グリコール酸、グルクロン酸、アスコルビン酸、ニコチン酸、サリチル酸などの有機酸塩などが挙げられる。さらにはアスパラギン酸、グルタミン酸などの酸性アミノ酸付加塩などが挙げられる。 For example, mineral acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates and phosphates; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionate, tartaric acid, fumaric acid, maleic acid Examples of the acid include malic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, and organic acid salts such as salicylic acid. Furthermore, acidic amino acid addition salts such as aspartic acid and glutamic acid can be mentioned.
　本発明において、医薬的に許容される溶媒和物としては、例えば、水和物、アルコール和物の他、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン、クロロホルム、ジクロロエタン、ジクロロメタン、ジエチルエーテル、メチルｔ－ブチルエーテル、エチレングリコールモノメチルエーテル、エチレングリコールジメチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン、アセトン、メチルエチルケトン、イソブチルメチルケトン、トルエン、ベンゼン、ｏ－キシレン、ｍ－キシレン、ｐ－キシレン、酢酸エチル、酢酸プロピル、酢酸ブチル、炭酸プロピレン、炭酸ジエチル、炭酸ジメチル、ヘキサン、ペンタン、ヘプタン、オクタンおよびシクロヘキサンからなる群より選択される薬学的に許容される溶媒との溶媒和物などが挙げられる。これらの中では水和物が通常好ましい。ここで、化合物を合成する際に使用し残存した溶媒との溶媒和物も含まれる。 In the present invention, pharmaceutically acceptable solvates include, for example, hydrate, alcoholate, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, chloroform, dichloroethane, dichloromethane, diethyl ether Methyl t-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, isobutyl methyl ketone, toluene, benzene, o-xylene, m -Xylene, p-xylene, ethyl acetate, propyl acetate, butyl acetate, propylene carbonate, diethyl carbonate, dimethyl carbonate, hexane, Tan, heptane, etc. solvates with pharmaceutically acceptable solvents selected from the group consisting of octane and cyclohexane. Among these, hydrates are usually preferred. Here, the solvate with the solvent which was used when synthesize | combined the compound and remained is also included.
　構造式（１）～（４）で表現される化合物のＰＩ５Ｐ４Ｋβに対するIC50値は１μＭ未満と極めて小さい。少量のこれら化合物投与によって、ＰＩ５Ｐ４Ｋβを十分に機能阻害することが推測される。よって、構造式（１）～（４）で表現される化合物などの投与によってＰＩ５Ｐ４Ｋβの機能（特にＧＴＰａｓｅとしての機能および／またはＧＴＰセンサーとしての機能）を阻害することが可能と考えられる。 The IC 50 values for PI5P4Kβ of the compounds represented by structural formulas (1) to (4) are extremely small, less than 1 μM. It is speculated that administration of a small amount of these compounds sufficiently inhibits PI5P4Kβ. Therefore, it is considered possible to inhibit the function of PI5P4Kβ (in particular, the function as a GTPase and / or the function as a GTP sensor) by administration of compounds represented by structural formulas (1) to (4).
　さらにこれら化合物は、ＰＩ５Ｐ４ＫαよりもＰＩ５Ｐ４Ｋβに強く作用する点で有利である。より具体的には、ＰＩ５Ｐ４ＫβのファミリーであるＰＩ５Ｐ４Ｋαに対するIC50値はそれぞれ、化合物（１）は２００μＭ以上、化合物（２）は２０μＭ以上、化合物（３）は１００μＭ以上、化合物（４）は４０μＭ以上である。いずれの化合物もＰＩ５Ｐ４Ｋβに対するIC50値は１μＭ未満であることから、ＰＩ５Ｐ４ＫαとＰＩ５Ｐ４ＫβとではＰＩ５Ｐ４Ｋβに極めて選択的に作用することが確認できた。 Furthermore, these compounds are advantageous in that they exert stronger action on PI5P4Kβ than PI5P4Kα. More specifically, the IC50 values for PI5P4Kα, a family of PI5P4Kβ, are 200 μM or more for compound (1), 20 μM or more for compound (2), 100 μM or more for compound (3), and 40 μM or more for compound (4) is there. It was confirmed that PI5P4Kβ and PI5P4Kβ act extremely selectively on PI5P4Kβ because all compounds have an IC50 value of less than 1 μM against PI5P4Kβ.
　なお、確認的に説明するが、IC50値は、阻害対象の活性を半減させることが可能な濃度を意味する。つまりIC50値が小さいほど阻害能力が高い。 In addition, although it demonstrates conclusively, an IC50 value means the density | concentration which can halve the activity of inhibition object. That is, the smaller the IC50 value, the higher the inhibition ability.
　上述の通り、ＰＩ５Ｐ４ＫβはＧＴＰセンサーとして機能する。上記阻害剤によってＰＩ５Ｐ４Ｋβのこの機能を阻害することで、ＰＩ５Ｐ４Ｋβが関与する（あるいはＰＩ５Ｐ４Ｋβが起点となる）ＧＴＰセンサー機構の解析（例えばシグナル伝達に関与する因子や様式の特定）に利用できる。したがって、本発明のＰＩ５Ｐ４Ｋβ阻害剤は、ＰＩ５Ｐ４Ｋβが関与するＧＴＰセンサー機構の解析用試薬の有効成分として使用することができる。 As mentioned above, PI5P4Kβ functions as a GTP sensor. By inhibiting this function of PI5P4Kβ by the above-mentioned inhibitor, it can be used for analysis of GTP sensor mechanism involving PI5P4Kβ (or starting from PI5P4Kβ) (for example, identification of a factor or mode involved in signal transduction). Therefore, the PI5P4Kβ inhibitor of the present invention can be used as an active ingredient of a reagent for analysis of GTP sensor mechanism involving PI5P4Kβ.
　本発明の解析用試薬は、有効成分として、上述したＰＩ５Ｐ４Ｋβ阻害剤を含有する。この阻害剤以外にも、任意の成分を含んでもよい。 The analysis reagent of the present invention contains the above-mentioned PI5P4Kβ inhibitor as an active ingredient. Other than this inhibitor, any component may be included.
　また上述の通り、ＰＩ５Ｐ４Ｋβは腫瘍形成の重要因子である。ＰＩ５Ｐ４Ｋβの機能阻害はひいては、ｐ５３遺伝子変異細胞の腫瘍化もしくはがん化（腫瘍の悪性化）の予防（完全予防および遅延化のいずれも意味する）、ｐ５３遺伝子変異細胞、ｐ５３遺伝子変異細胞を含む腫瘍もしくはがんの増殖の予防（完全停止および低速化のいずれも意味する）、あるいはｐ５３遺伝子変異腫瘍もしくはがんの治療（根治および緩和のいずれも意味する）に繋がるものと推測される。したがって、本発明のＰＩ５Ｐ４Ｋβ阻害剤は抗腫瘍剤の有効成分として使用することができる。 Also, as mentioned above, PI5P4Kβ is an important factor in tumorigenesis. The functional inhibition of PI5P4Kβ in turn includes the prevention (both complete prevention and delay) of tumorigenesis or carcinogenesis (malignancy of tumor) of p53 gene mutant cells, p53 gene mutant cells, p53 gene mutant cells It is speculated that it will lead to the prevention of tumor or cancer growth (meaning both complete arrest and slowing down) or treatment of p53 gene mutated tumor or cancer (meaning both cure and alleviation). Therefore, the PI5P4Kβ inhibitor of the present invention can be used as an active ingredient of an antitumor agent.
　本発明の抗腫瘍剤は、有効成分として、上述したＰＩ５Ｐ４Ｋβ阻害剤を含有する。この阻害剤以外にも、医薬的に許容される限り任意の成分を含んでもよい。 The antitumor agent of the present invention contains the PI5P4Kβ inhibitor described above as an active ingredient. Other than this inhibitor, any component may be included as long as it is pharmaceutically acceptable.
　本発明において『有効成分として含有する』とは、解析用試薬または抗腫瘍剤の所定の投与量において所望の効果を得られる程度の量のＰＩ５Ｐ４Ｋβ阻害剤を投与できることを意味する。 In the present invention, “containing as an active ingredient” means that a PI5P4Kβ inhibitor can be administered in an amount such that a desired effect can be obtained at a predetermined dose of an analysis reagent or an antitumor agent.
　あくまで目安であるが、抗腫瘍剤として生物に投与する場合、本発明の阻害剤の投与量は、１日当たり、且つ、体重１ｋｇあたり、０．００１ｍｇ以上、０．０１ｍｇ以上、０．１ｍｇ以上、０．５ｍｇ以上、または１ｍｇ以上となるように薬剤中の含有量が決定されることが好ましい。他方、あくまで目安であるが、本発明の阻害剤の投与量が、１日当たり、且つ、体重１ｋｇあたり、１００ｍｇ以下、１０ｍｇ以下、９ｍｇ以下、８ｍｇ以下、７ｍｇ以下、６ｍｇ以下、５ｍｇ以下、４ｍｇ以下、または３ｍｇ以下となるように薬剤中の含有量が決定されることが好ましい。 The dose of the inhibitor of the present invention is 0.001 mg or more, 0.01 mg or more, and 0.1 mg or more per kg of body weight per day and when it is administered to an organism as an antitumor agent, although it is a guide to the last. The content in the drug is preferably determined to be 0.5 mg or more or 1 mg or more. On the other hand, the dose of the inhibitor of the present invention is 100 mg or less, 10 mg or less, 9 mg or less, 8 mg or less, 7 mg or less, 6 mg or less, 5 mg or less, 4 mg or less per day and per kg body weight Preferably, the content in the drug is determined to be 3 mg or less.
　解析用試薬または抗腫瘍剤におけるＰＩ５Ｐ４Ｋβ阻害剤の含有量は、解析用試薬全量基準または抗腫瘍剤全量基準で、通常は、１～９０質量％である。２質量％以上、３質量％以上、４質量％以上、５質量％以上、６質量％以上、７質量％以上、８質量％以上、９質量％以上、１０質量％以上、１５質量％以上、２０質量％以上、２５質量％以上、３０質量％以上としてもよい。他方、８５質量％以下、８０質量％以下、７５質量％以下、７０質量％以下、６５質量％以下、６０質量％以下、５５質量％以下、５０質量％以下、４５質量％以下としてもよい。 The content of the PI5P4Kβ inhibitor in the analysis reagent or the antitumor agent is usually 1 to 90% by mass, based on the total amount of the analysis reagent or the total amount of the antitumor agent. 2 mass% or more, 3 mass% or more, 4 mass% or more, 5 mass% or more, 6 mass% or more, 7 mass% or more, 8 mass% or more, 9 mass% or more, 10 mass% or more, 15 mass% or more, It is good also as 20 mass% or more, 25 mass% or more, and 30 mass% or more. On the other hand, 85% by mass, 80% by mass, 75% by mass, 70% by mass, 65% by mass, 60% by mass, 55% by mass, 50% by mass, 45% by mass or less.
　本発明の抗腫瘍剤は、微小管集合阻害剤、ＡＫＴ阻害剤、ｍＴＯＲ阻害剤、ＭＥＫ阻害剤、ＲＴＫ阻害剤、ＡＴＭ阻害剤、ＡＴＲ阻害剤、ＰＩ３Ｋ阻害剤、ＥＧＦＲ阻害剤、Ｂ－Ｒａｆ阻害剤、Ｃ－ｋｉｔ阻害剤、ＰＡＲＰ阻害剤、ＤＮＡ架橋剤、ＤＮＡ挿入剤、およびシチジン類似体から成る群より選択される１以上の剤をさらに含有しても良い。 The antitumor agent of the present invention is a microtubule assembly inhibitor, AKT inhibitor, mTOR inhibitor, MEK inhibitor, RTK inhibitor, ATM inhibitor, ATR inhibitor, PI3K inhibitor, EGFR inhibitor, B-Raf inhibition It may further contain one or more agents selected from the group consisting of agents, C-kit inhibitors, PARP inhibitors, DNA crosslinkers, DNA intercalators, and cytidine analogs.
　本発明の抗腫瘍剤は、所望により、着色剤、保存剤、香料、風味剤、甘味剤などの医薬的に許容される添加物や他の治療薬を含有させることができる。 The antitumor agent of the present invention can optionally contain pharmaceutically acceptable additives such as coloring agents, preservatives, flavors, flavors, sweeteners and other therapeutic agents.
　本発明の抗腫瘍剤の製剤化に際しては、医薬的に許容される安定化剤を配合することが好ましい。そのような安定化剤としては、例えば、アルブミン、グロブリン、ゼラチン、マンニトール、グルコース、デキストラン、エチレングリコールなどが挙げられる。 When formulating the antitumor agent of the present invention, it is preferable to incorporate a pharmaceutically acceptable stabilizer. Such stabilizers include, for example, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like.
　本発明の抗腫瘍剤は、さらに任意の成分として、医薬的に許容される任意の希釈液、担体、賦形剤などを含んでもよい。 The antitumor agent of the present invention may further contain, as an optional component, any pharmaceutically acceptable diluent, carrier, excipient and the like.
　本発明の抗腫瘍剤を適用する対象はｐ５３遺伝子変異を伴う変異細胞を含む腫瘍（好ましくはＰＩ５Ｐ４Ｋβの活性向上が認められるもの）であれば特に限定されない。腫瘍は悪性腫瘍（がん）であってもよい。 The subject to which the antitumor agent of the present invention is to be applied is not particularly limited as long as it is a tumor containing a mutant cell with a p53 gene mutation (preferably, one that shows an improvement in the activity of PI5P4Kβ). The tumor may be a malignant tumor (cancer).
　腫瘍やがんとしては、例えば、大腸がん、直腸結腸がん、胃がん、肺がん、膵がん、前立腺がん、腎臓がん、甲状腺がん、乳がん、胆道がん、白血病、脳悪性腫瘍、リンパ腫、骨肉腫、骨髄腫、脳腫瘍などが挙げられる。 Examples of tumors and cancers include colon cancer, colorectal cancer, stomach cancer, lung cancer, pancreatic cancer, prostate cancer, kidney cancer, thyroid cancer, breast cancer, biliary cancer, leukemia, brain cancer, Lymphoma, osteosarcoma, myeloma, brain tumor and the like.
　本発明の抗腫瘍剤は、任意の剤型に製剤化することができる。剤型としては、例えば、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、懸濁剤、座剤、軟膏、クリーム剤、ゲル剤、貼付剤、吸入剤、注射剤などが挙げられる。 The antitumor agent of the present invention can be formulated into any dosage form. Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, injections and the like.
　本発明の抗腫瘍剤は、経口投与、腹腔内投与、皮内投与、静脈内投与、筋肉内投与、脳内投与など任意の方法によって投与してよい。 The antitumor agent of the present invention may be administered by any method such as oral administration, intraperitoneal administration, intradermal administration, intravenous administration, intramuscular administration, intracerebral administration and the like.
　本発明の抗腫瘍剤の投与量は、投与対象者の症状、年齢、性別、抗腫瘍剤の成分などにより適宜調整されるものである。 The dose of the antitumor agent of the present invention is appropriately adjusted according to the condition, age, sex, components of the antitumor agent, and the like of the subject of administration.
　本発明のＰＩ５Ｐ４Ｋβ阻害剤は、腫瘍やがん以外にも、ＰＩ５Ｐ４Ｋβの機能（特にＧＴＰセンサーとしての機能および／またはＧＴＰａｓｅとしての機能）が亢進することで生じる又は悪化する疾病に使用可能である。このような疾病として、糖尿病などが挙げられる。したがって本発明の阻害剤は、糖尿病などの代謝疾病の予防薬ないし治療薬の有効成分として使用することが可能である。 The PI5P4Kβ inhibitor of the present invention can be used for diseases caused or exacerbated by enhancement of the function of PI5P4Kβ (in particular, the function as a GTP sensor and / or the function as a GTPase) other than tumors and cancers. Such diseases include diabetes. Therefore, the inhibitor of the present invention can be used as an active ingredient of a preventive or therapeutic agent for metabolic diseases such as diabetes.
　以下に実施例を挙げて本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。　 EXAMPLES The present invention will be specifically described by way of the following examples, but the present invention is not limited to these examples.
　まず、特開２０１７－０４０６０３号公報（発明の名称「ＮＭＲを用いた薬剤のスクリーニング方法」）に開示された手法に準じて、ＰＩ５Ｐ４Ｋβ阻害化合物を探索した。対象とした化合物は、Pharmakon-1600の化合物１６００種およびMSM-MTS法（Fukunishi, Y. Mikami, S. Kubota, H. Nakamura, “Multiple target screening method for robust and accurate in silico screening.” Journal of Molecular Graphics and Modelling, 25, 61-70 (2005); Y. Fukunishi, S. Kubota, H. Nakamura, “Noise reduction method for molecular interaction energy: application to in silico drug screening and in silico target protein screening”, Journal of Chemical Information and Modeling, 46, 2071-2084 (2006))を用いた２００万化合物のin silicoスクリーニングから選定した候補化合物１１６７種である。 First, PI5P4Kβ inhibitory compounds were searched according to the method disclosed in Japanese Patent Application Laid-Open No. 2017-040603 (name of the invention “Method for screening a drug using NMR”). The compounds targeted are the Pharmakon-1600 compound 1600 and the MSM-MTS method (Fukunishi, Y. Mikami, S. Kubota, H. Nakamura, “Multiple target screening method for accurate and accurate in silico screening.” Journal of Molecular Graphics and Modeling, 25, 61-70 (2005); Y. Fukunishi, S. Kubota, H. Nakamura, “Noise reduction method for molecular interaction energy: application to silico drug screening and in silico target protein screening”, Journal of the These are candidate compounds 1167 selected from in silico screening of 2 million compounds using Chemical Information and Modeling, 46, 2071-2084 (2006)).
　Pharmakon-1600の化合物１６００種について、特開２０１７－０４０６０３号公報（発明の名称「ＮＭＲを用いた薬剤のスクリーニング方法」）に開示された手法に準じて、ＰＩ５Ｐ４Ｋβ阻害化合物を探索した結果、同定された化合物の１つが化合物（３）である。
Figure JPOXMLDOC01-appb-C000013
 As a result of searching for a PI5P4Kβ inhibiting compound according to the method disclosed in JP-A-2017-040603 (name of the invention “Method for screening a drug using NMR”), about 1600 compounds of Pharmakon-1600 are identified as a result of searching One of the above compounds is the compound (3).
Figure JPOXMLDOC01-appb-C000013
　in silicoスクリーニングから選定した候補化合物１１６７種についても同様に、特開２０１７－０４０６０３号公報に開示された手法に準じて解析を行った。 Similarly, analysis was performed on the candidate compounds 1167 selected from in silico screening according to the method disclosed in JP-A-2017-040603.
　その結果同定された化合物の１つが下記構造式（ｉ）で表現される化合物である。以下化合物（ｉ）とも呼称する。
Figure JPOXMLDOC01-appb-C000014
 One of the compounds identified as a result is a compound represented by the following structural formula (i). Hereinafter, it is also referred to as compound (i).
Figure JPOXMLDOC01-appb-C000014
　次に、同定された阻害化合物のIC50値を得るため、化合物（ｉ）については１．８μＭ～６０μＭ（２倍希釈系列）、化合物（３）については１．３μＭ～２０μＭ（２倍希釈系列）の希釈系列を２５μＬずつ作成した。反応液として、２５０μＭのＧＴＰ、１．５μＭのＰＩ５Ｐ４Ｋβを１０ｍＭのＰｈｏｓｐｈａｔｅ（ｐＨ７．５）、１００ｍＭのＮａＣｌ、１０ｍＭのＭｇＣｌ２に溶解させた反応液を調製した。化合物の溶液２５μＬと、反応液５００μＬと混合し、２５℃で２０時間反応を行った。各サンプル中のＤＭＳＯ濃度は５％となるように調整した。 Next, in order to obtain an IC 50 value of the identified inhibitory compound, 1.8 μM to 60 μM (2-fold dilution series) for compound (i), 1.3 μM to 20 μM (2-fold dilution series) for compound (3) 25 μL of each dilution series was prepared. As a reaction solution, a reaction solution in which 250 μM of GTP, 1.5 μM of PI5P4Kβ were dissolved in 10 mM of Phosphate (pH 7.5), 100 mM of NaCl, and 10 mM of MgCl 2 was prepared. 25 μL of the compound solution and 500 μL of the reaction solution were mixed, and reacted at 25 ° C. for 20 hours. The DMSO concentration in each sample was adjusted to 5%.
　対照として、下記構造式（ａ）で表現される化合物についても同様に解析を行った。以下、この化合物を化合物（ａ）とも呼称する。これは本願が提示した非特許文献１に記載されている、ＰＩ５Ｐ４ＫαやＰＩ５Ｐ４Ｋβを阻害できる化合物の１つである。この化合物については、１．８μＭ～１２０μＭ（２倍希釈系列）の濃度希釈系列を作成した。 As a control, analysis was similarly performed on a compound represented by the following structural formula (a). Hereinafter, this compound is also referred to as compound (a). This is one of the compounds which can inhibit PI5P4Kα or PI5P4Kβ described in Non-Patent Document 1 presented in the present application. For this compound, a concentration dilution series of 1.8 μM to 120 μM (2-fold dilution series) was prepared.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　ＧＤＰ／ＧＴＰ比の濃度依存性からIC50値を算出した結果、化合物（ｉ）のIC50値は１．４μＭ、化合物（３）のIC50値は０．５７μＭ、化合物（ａ）のIC50値は４．７μＭであり、化合物（ｉ）および化合物（３）は従来周知なＰＩ５Ｐ４Ｋβ阻害化合物（ａ）よりも強い阻害活性を示すことが明らかとなった（図２）。さらに本願が提示した非特許文献２に記載されているＰＩ５Ｐ４Ｋβ阻害化合物ＳＡＲ０８８（下記構造式（ｂ）で表現される化合物、以下化合物（ｂ）とも呼称する）のIC50値は３．８μＭと記載されており、これと比べても優れている。つまり、化合物（ｉ）および化合物（３）は、従来のＰＩ５Ｐ４Ｋβ阻害化合物よりも高い阻害活性を示すことが明らかとなった。 As a result of calculating the IC50 value from the concentration dependency of the GDP / GTP ratio, the IC50 value of compound (i) is 1.4 μM, the IC50 value of compound (3) is 0.57 μM, and the IC50 value of compound (a) is 4. The concentration was 7 μM, and it became clear that the compound (i) and the compound (3) exhibited stronger inhibitory activity than the conventionally known PI5P4Kβ inhibitor compound (a) (FIG. 2). Furthermore, the IC50 value of PI5P4Kβ inhibitor compound SAR088 (a compound represented by the following structural formula (b), hereinafter also referred to as compound (b)) described in Non-patent document 2 presented in the present application is described as 3.8 μM Better than this. That is, it became clear that the compound (i) and the compound (3) show higher inhibitory activity than the conventional PI5P4Kβ inhibitory compound.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　また化合物（ｉ）については、水溶液中での互変異性が見つかったことから、これを安定化するため、安定化化合物（下記化合物（４））を作成した。同様に解析したところ、この化合物のIC50値は０．７１μＭであり、活性がさらに強化されたことが確認できた（図３）。
Figure JPOXMLDOC01-appb-C000017
 In addition, since the compound (i) was found to have tautomerism in an aqueous solution, in order to stabilize it, a stabilized compound (the following compound (4)) was prepared. Similar analysis revealed that the IC50 value of this compound was 0.71 μM, confirming that the activity was further enhanced (FIG. 3).
Figure JPOXMLDOC01-appb-C000017
　化合物（３）および化合物（４）について、出願人らが提唱した方法（Sumita, K. et al. The Lipid Kinase PI5P4Kβ; Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis. Molecular Cell 61, 187-198 (2016), Miki Senda, Use of Multiple Cryoprotectants to Improve Diffraction Quality from Protein CrystalsCryst. Growth Des., 2016, 16 (3), pp 1565-1571）に則り、結晶構造解析を行った。その結果、いずれの化合物もＰＩ５Ｐ４ＫβのＧＴＰ結合ポケットに結合し、競合的に酵素反応を阻害することが明らかとなった。そして阻害に際しこれら化合物は異なる位置に結合することもわかった。この知見から、相対位置に基づき、これら化合物の構造をつなぎ合わせた化合物（Link compound）を設計した（図４参照）。化合物（１）および（２）はこのLink compoundに構造的に類似している。これらについても同様にIC50値を解析した。
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-I000019
For the compound (3) and the compound (4), the method proposed by the applicants (Sumita, K. et al. The Lipid Kinase PI5P4Kβ; Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis. Molecular Cell 61, 187-198 (2016 Crystal structure analysis was performed according to Miki Senda, Use of Multiple Cryoprotectants to Improve Diffraction Quality from Protein Crystals Cryst. Growth Des., 2016, 16 (3), pp 1565-1571). As a result, it became clear that all compounds bind to the GTP binding pocket of PI5P4Kβ and competitively inhibit the enzyme reaction. It was also found that these compounds bind to different positions upon inhibition. From this finding, based on the relative position, a compound (Link compound) in which the structures of these compounds were connected was designed (see FIG. 4). Compounds (1) and (2) are structurally similar to this Link compound. The IC50 values were similarly analyzed for these.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-I000019
　その結果、化合物（１）および化合物（２）は、ＮＭＲにより活性を評価可能な最低濃度である０．５μＭで既にＰＩ５Ｐ４Ｋβの活性をそれぞれ１０％未満および４０％未満に低下させることがわかった。すなわちそのIC50値は０．５μＭを下回っている。 As a result, it was found that Compound (1) and Compound (2) already reduced the activity of PI5P4Kβ to less than 10% and less than 40%, respectively, at 0.5 μM which is the lowest concentration at which the activity can be evaluated by NMR. That is, its IC50 value is less than 0.5 μM.
　以上のことから、化合物（１）～（４）はいずれも、ＰＩ５Ｐ４ＫβのＧＴＰ部位に結合する化合物であり、ＰＩ５Ｐ４ＫβのＧＴＰａｓｅとしての機能および／またはＧＴＰセンサーとしての機能を阻害可能な化合物であることがわかった。またそのIC50値は１μＭ未満と従来の阻害化合物よりも有意に強い阻害活性を示す（図５）。これらの化合物によるＰＩ５Ｐ４Ｋβの機能阻害はＧＴＰセンサー機構の解析に有用である。またＧＴＰセンサーＰＩ５Ｐ４Ｋβの阻害を介して抗腫瘍活性を発揮することが期待される。さらにＰＩ５Ｐ４Ｋβの機能が亢進することによって生じるおよび／または悪化する疾病に対しても、これら化合物が予防や治療に使用できることが期待される。加えてこれらの化合物は、ＰＩ５Ｐ４Ｋβに対するIC50値が小さい一方、ＰＩ５Ｐ４Ｋαに対するIC50値はＰＩ５Ｐ４Ｋβに対するIC50値と比較して十分大きく、ＰＩ５Ｐ４Ｋαの阻害は起こしにくい点で有利である。 From the above, each of the compounds (1) to (4) is a compound that binds to the GTP site of PI5P4Kβ, and is a compound capable of inhibiting the function of PI5P4Kβ as the GTPase and / or the function as the GTP sensor I understand. Also, its IC50 value shows significantly stronger inhibitory activity than the conventional inhibitory compounds, less than 1 μM (FIG. 5). Functional inhibition of PI5P4Kβ by these compounds is useful for analysis of GTP sensor mechanism. It is also expected to exert anti-tumor activity through the inhibition of the GTP sensor PI5P4Kβ. Furthermore, it is expected that these compounds can be used for prevention and treatment of diseases caused and / or deteriorated by enhancement of the function of PI5P4Kβ. In addition, these compounds are advantageous in that the IC50 value against PI5P4Kβ is small, while the IC50 value against PI5P4Kα is sufficiently large compared to the IC50 value against PI5P4Kβ, and inhibition of PI5P4Kα is less likely to occur.

Claims (6)

  1. 　下記構造式（１）～（４）で表現される化合物およびこれら化合物の医薬的に許容される塩、並びにそれらの医薬的に許容される溶媒和物から成る群より選択される少なくとも１つを有効成分として含有するＰＩ５Ｐ４Ｋβ阻害剤。
    Figure JPOXMLDOC01-appb-I000001
    Figure JPOXMLDOC01-appb-I000002
    Figure JPOXMLDOC01-appb-I000003
    Figure JPOXMLDOC01-appb-I000004
    At least one selected from the group consisting of compounds represented by the following structural formulas (1) to (4) and pharmaceutically acceptable salts of these compounds, and pharmaceutically acceptable solvates thereof: PI5P4K beta inhibitor which contains as an active ingredient.
    Figure JPOXMLDOC01-appb-I000001
    Figure JPOXMLDOC01-appb-I000002
    Figure JPOXMLDOC01-appb-I000003
    Figure JPOXMLDOC01-appb-I000004
  2. 　請求項１に記載の阻害剤を使用してＰＩ５Ｐ４ＫβのＧＴＰセンサーとしての機能を阻害する方法。 A method for inhibiting the function of PI5P4Kβ as a GTP sensor using the inhibitor according to claim 1.
  3. 　請求項１に記載の阻害剤を有効成分として含有する、ＰＩ５Ｐ４Ｋβが関与するＧＴＰセンサー機構の解析に用いられる試薬組成物。 A reagent composition for analysis of a GTP sensor mechanism involving PI5P4Kβ, which comprises the inhibitor according to claim 1 as an active ingredient.
  4. 　請求項１に記載の阻害剤を有効成分として含有する抗腫瘍剤組成物。 An antitumor agent composition comprising the inhibitor according to claim 1 as an active ingredient.
  5. 　請求項２に記載の方法を利用して、または請求項４に記載の抗腫瘍剤組成物を投与して、腫瘍の発生、増殖および／または悪性化を予防ないし治療する方法。 A method for preventing or treating tumor development, growth and / or malignancy, using the method according to claim 2 or administering the antitumor agent composition according to claim 4.
  6. 　請求項１に記載の阻害剤を有効成分として含有する、ＰＩ５Ｐ４Ｋβの機能亢進に関する疾病を予防ないし治療するための医薬組成物。 A pharmaceutical composition comprising the inhibitor according to claim 1 as an active ingredient, for preventing or treating a disease associated with PI5P4Kβ hyperfunction.
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