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WO2019111792A1 - INHIBITEUR DE LA PROTÉINE PI5P4Kβ DÉTECTRICE DE GTP - Google Patents

INHIBITEUR DE LA PROTÉINE PI5P4Kβ DÉTECTRICE DE GTP 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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PCT/JP2018/043919
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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.

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Abstract

[Problème] Fournir un inhibiteur de PI5P4Kβ comprenant une IC50 inférieure à celle des inhibiteurs classiques et capable d'inhiber fortement PI5P4Kβ. [Solution] L'invention porte sur un inhibiteur de PI5P4Kβ contenant, en tant que composant efficace, au moins un composé choisi dans le groupe constitué par les composés représentés par les formules développées (1) à (4), des sels de ceux-ci de qualité pharmaceutique, et des solvates de ceux-ci de qualité pharmaceutique.
PCT/JP2018/043919 2017-12-05 2018-11-29 INHIBITEUR DE LA PROTÉINE PI5P4Kβ DÉTECTRICE DE GTP WO2019111792A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
CN101985428A (zh) * 2009-07-29 2011-03-16 杭州民生药业有限公司 邻苯胺基苯甲酸衍生物或其药学上可接受的盐、其制备方法及其用途
JP2013535448A (ja) * 2010-07-20 2013-09-12 コーニング インコーポレイテッド ＧＰＲ３５および／またはＧＰＲ３５−ｈＥＲＧ複合体に関連する病的状態の治療のための組成物および方法
JP2016530317A (ja) * 2013-09-11 2016-09-29 ジ・アドミニストレーターズ・オブ・ザ・チューレーン・エデュケーショナル・ファンド 新規アントラニルアミドとその使用
JP2017040603A (ja) * 2015-08-21 2017-02-23 国立研究開発法人産業技術総合研究所 Ｎｍｒを用いた薬剤のスクリーニング方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101985428A (zh) * 2009-07-29 2011-03-16 杭州民生药业有限公司 邻苯胺基苯甲酸衍生物或其药学上可接受的盐、其制备方法及其用途
JP2013535448A (ja) * 2010-07-20 2013-09-12 コーニング インコーポレイテッド ＧＰＲ３５および／またはＧＰＲ３５−ｈＥＲＧ複合体に関連する病的状態の治療のための組成物および方法
JP2016530317A (ja) * 2013-09-11 2016-09-29 ジ・アドミニストレーターズ・オブ・ザ・チューレーン・エデュケーショナル・ファンド 新規アントラニルアミドとその使用
JP2017040603A (ja) * 2015-08-21 2017-02-23 国立研究開発法人産業技術総合研究所 Ｎｍｒを用いた薬剤のスクリーニング方法

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* Cited by examiner, † Cited by third party
Title
ABDELRAHIM, MAEN ET AL.: "Tolfenamic Acid and Pancreatic Cancer Growth, Angiogenesis, and Sp Protein Degradation", J. NATL. CANCER INST., vol. 98, no. 12, 2006, pages 855 - 868, XP002667993 *
PATHI, SATYA ET AL.: "Tolfenamic Acid Inhibits Colon Cancer Cell and Tumor Growth and InduceE Degradation of Specificity Protein (Sp) Transcription Factors", MOL. CARCINOG., vol. 53, 2014, pages E53 - E61, XP055616391 *
VOSS, D. MARC ET AL.: "Discovery and pharmacological characterization of a novel small molecule inhibitor of phosphatidylinositol-5- phosphate 4-kinase, type II, beta", BIOCHEM. BIOPHYS. RES. COMMUN., vol. 449, 2014, pages 327 - 331, XP028868284 *

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