JP2022509657A - Plk1の活性抑制剤を有効成分として含む癌の予防または治療用薬学的組成物 - Google Patents
Plk1の活性抑制剤を有効成分として含む癌の予防または治療用薬学的組成物 Download PDFInfo
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- cancer
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 210000001850 polyploid cell Anatomy 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
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- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- NUFKRPFBEWPTNT-UHFFFAOYSA-N pteridine-7-carboxylic acid Chemical compound C1=NC=NC2=NC(C(=O)O)=CN=C21 NUFKRPFBEWPTNT-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000019203 rebaudioside A Nutrition 0.000 description 1
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- 229920005989 resin Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
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Images
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- 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
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
Abstract
Description
R3は、H、ハロゲン、-NH2、アルキル、または-CH=Oであり、R4は、H、アルキル、-COOH、または-CX3であり、Xは、ハロゲンである)
R1は、H、-CH3、または-CH2COOHであり、
R2は、H、-CH3、-C2H4CN、-CH2(CH(OH))3CH2OH、-CH2(CH(OH))3OPH2O3または
R3は、H、Cl、-NH2、-CH3、または-CH=Oであり、
R4は、H、-CH3、-COOH、または-CF3でありうる。
10-methyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-chloro-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
10-methyl-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-amino-1,3-dimethyl-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
8-amino-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8,10-trimethyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,10-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridine-8-carbaldehyde;
4,10-Dihydro-7,8,10-trimethyl-2,4-dioxobenzo[g]pteridine-3(2H)-acetic Acid;
3-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}propanenitrile;
10-[2-(3-methylphenoxy)ethyl]-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine-2,4-dione;および
[(2R,3S,4S)-5-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl]dihydrogen phosphate
R1は、H、アルキル、または-CnH2nCOOH(nは1~4の整数)であり、
R2は、H、アルキル、-CmH2mCN、-CmH2mOR5、または-CpH2p(CH(OH))qR6であり、R5は、1つ以上のC1-3のアルキルで置換されたフェニルであり、R6は、H、アルキルまたは-OPH2O3であり、mは、2~4の整数であり、pは、1~3の整数であり、qは、2~4の整数であり、
R3は、H、ハロゲン、-NH2、アルキル、または-CH=Oであり、
R4は、H、アルキル-COOH、または-CX3であり、Xは、ハロゲンである。
R1は、H、-CH3、または-CH2COOHであり、
R2は、H、-CH3、-C2H4CN、-CH2(CH(OH))3CH2OH、-CH2(CH(OH))3OPH2O3または
R3は、H、Cl、-NH2、-CH3、または-CH=Oであり、
R4は、H、-CH3、-COOH、または-CF3でありうる。
10-methyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-chloro-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
10-methyl-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-amino-1,3-dimethyl-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
8-amino-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8,10-trimethyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,10-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridine-8-carbaldehyde;
4,10-Dihydro-7,8,10-trimethyl-2,4-dioxobenzo[g]pteridine-3(2H)-acetic Acid;
3-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}propanenitrile;
10-[2-(3-methylphenoxy)ethyl]-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine-2,4-dione;および
[(2R,3S,4S)-5-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl]dihydrogen phosphate
本発明者らは、以前の研究を通じてNCAPG2の1010番目に位置するリン酸化したスレオニン(Threonine)を中心とするGVLSpTLIペプチドがPLK1(Serine/threonine-protein kinase 1)の基質結合部位であるPBD(polo-box domain)ドメインに結合し、前記結合がPLK1の細胞***期の作用に非常に重要な紡錘糸と染色体の結合部位に位置するようにすることを糾明し、その結晶構造を解析した。このような研究結果を基に前記ペプチドのPBD結合構造をシミュレートし、PBDに競争的に結合できる低分子化合物を発掘しようとした。
1次および2次化合物のスクリーニングを通じて発掘された化合物およびhit compoundおよびその多様な誘導体に対して前記実施例1に示すFP assayを実施して、化合物のIC50を分析しようとした。このために、GST resinを利用してGST-tagが結合された標的タンパク質を分離し、最後にgel filtrationを行って、GST-tagが結合された純粋な標的タンパク質15mg/mlを得た。reaction bufferで前記標的タンパク質をそれぞれ12uM、3uM、および1.5uMの濃度で希釈して準備し、茶色チューブに保管されたFITCが結合されたペプチド(FITC-labeled 1010pT(GVLS-pT-LI-NH2))は、reaction bufferで希釈して、30nMの濃度で準備した。また、前記100mMの濃度の化合物は、reaction bufferでそれぞれ160.0uM、80.0uM、40.0uM、20.0uM、10.0uM、5.0 uM、2.5uM、1.25uM、0.625uM、0.3125uM、0.15625uM、0.0uMで希釈して準備した。次に、前記標的タンパク質を96ウェルブラックプレートに3つの濃度をそれぞれ12個のウェル、すなわちそれぞれ12ウェルずつ3ラインに分注し、結合ペプチドを標的タンパク質が分注された各ウェルに分注して混合した。その後、標的タンパク質と結合ペプチドが混合された各ウェルに前記化合物を濃度別にそれぞれ分注して常温で30分間反応させた。反応が完了すると、Infinte F200 Pro(TECAN Group Ltd、switzerland)を利用して485nmのExcitation波長および535nmのEmission波長に設定し、G-Factorは、1.077にして、蛍光偏光値を測定した。この際、G-Factorは、ペプチドの特性によって少しずつ差異があるので、実験開始前にペプチドのみをサンプリングして、値を固定させた後、使用した。Binding curvesは、Graphpad Prism(GraphPad Software、San Diego、CA、USA)を利用して分析した。
前記実施例1および2を通じて発掘したPLK1のPBDドメインに特異的に結合する化合物が実際に癌細胞の***時にPLK1に結合することによって、細胞の***を抑制して成長を阻害するかを調べてみようとした。
前記化合物を処理したとき、細胞内部でのPLK1位置の変化があるかを確認するために、中心体に位置するr-tubulinとPLK1、染色体(DAPI)の相互位置関係を確認した。
前記化合物2(M2)を処理したとき、細胞周期に及ぼす影響を確認するために、フローサイトメトリー装備を利用した。前記化合物2(M2)を肝癌細胞株の1つのSNU-449細胞に1日および3日後、それぞれ20、40、および80μMの濃度で処理し、さらに2日後、harvestした。
培養培地が添加された96ウェルマイクロタイトプレートで肝細胞癌腫細胞株であるHEPG2細胞は、hit compoundの濃度ごとに4~6コピーでプレーティングされた。DMSOに溶解したhit compoundは、実験設計によって翌日添加し、シーディング(seeding)された細胞数は、細胞対照群で処理したプロトコルの最終日に80%に達した細胞密度により決定された。細胞シーディング24時間後、細胞に多様な濃度のhit compound(M2およびBI2536)を処理し、1次処理48時間後、培地を吸引した後、2次処理した。48時間後、37℃で30分間、2.5μM Hoechst 33342染色を通じて細胞核を視覚化した後、培地を吸引し、新しい培地で洗浄した。CytationTM 3(BioTek、USA)を使用してプレートを読み取りし、細胞生存力を分析し、結果は、対照群処理と比較してhit compound処理後、生存細胞の相対的百分率で表示す。
M2に露出した細胞死形態を分析するために、肝細胞癌腫細胞株であるHEPG2細胞を20または100μMのM2および20または100nMのBI2536で3日間処理した。細胞死は、annexin V-fluorescein isothiocyanate(annexin V-FITC)と壊死性およびapoptosis細胞のpropidium iodide(PI)染色により検出された。まず、細胞を収穫し、PBSで1回洗浄した。その後、細胞をAnnexin V(BD、51-65874X)およびPI(BD、51-66211E)4μlが含まれた100μlの結合緩衝液に再懸濁した。細胞を暗所で37℃で15分間染色した後、FACSan(BD、San Jose、CA)を使用して細胞を分析した。データは、CELLQuestソフトウェア(BD)を使用して分析した。
化合物4(M21)を300μlのPBSに希釈して、それぞれマウス体重当たり1mg/kg、5mg/kgおよび10mg/kgで週3回腹腔注射し、対照群は、300 μlのPBSにDMSO希釈して3%で腹腔注射した。2週後にマウスを犠牲にして、肺、心臓、肝、腎臓、脾臓および皮膚を摘出してホルマリン溶液に固定した。固定した組織に対する組織病理学的分析で別途の急性毒性による変化は観察されなかった(図16)。
肝細胞癌腫細胞株であるHepG2を5×106でBalB/c Nude miceに背中皮膚に注入し、3週程度後、十分に癌組織が形成されると、これを摘出して、1mm3で一定に切って、1cm以内で腹部を切除し、肝の右側内側葉(right median lobe)に移植した。
ヒト肝癌から分離した癌組織をBalB/C Nude miceの皮膚組織に移植して癌組織に成長して、PDXモデルで確立した組織を利用して1mm3で一定に切って、1cm以内で腹部を切除し、肝の右側内側葉(right median lobe)に移植した。前記方法で20匹のBalB/C Nude miceに肝癌組織を移植後、10日程度後に、MRI映像に小さい点で確認されて、肝癌がよく保持された鼠類を対象に3つのグループに分け(図22a、図22bおよび図22c参照)、溶媒対照群(control、DMSO)と40mg/kgでhit(M2)物質とBI2536 4mg/kgを1.5%未満のDMSOを溶媒(vehicle)として腹腔に2日に1回ずつ注射し、1週間に1回ずつMRI映像で組織が一定に成長する鼠類を選定(follow up)した。そして、早く成長した癌組織が1cm以下でマウスを犠牲にして、癌組織を観察した(3週、11回の処置)。
Claims (12)
- 下記化学式1または2で表示される化合物またはその薬学的に許容可能な塩を有効成分として含む、癌の予防または治療用薬学的組成物。
R1は、H、アルキル、または-CnH2nCOOH(nは1~4の整数)であり、
R2は、H、アルキル、-CmH2mCN、-CmH2mOR5、または-CpH2p(CH(OH))qR6であり、R5は、1つ以上のC1-3のアルキルで置換されたフェニルであり、R6は、H、アルキルまたは-OPH2O3であり、mは、2~4の整数であり、pは、1~3の整数であり、qは、2~4の整数であり、
R3は、H、ハロゲン、-NH2、アルキル、または-CH=Oであり、
R4は、H、アルキル、-COOH、または-CX3であり、Xは、ハロゲンである。 - 前記化学式1または2で表示される化合物は、下記化合物よりなる群から選ばれることを特徴とする請求項1に記載の薬学的組成物:
2,4-Dioxo-1,2,3,4-tetrahydrobenzo[g]pteridine-7-carboxylic acid;
10-methyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-chloro-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
10-methyl-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-amino-1,3-dimethyl-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
8-amino-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8,10-trimethyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,10-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridine-8-carbaldehyde;
4,10-Dihydro-7,8,10-trimethyl-2,4-dioxobenzo[g]pteridine-3(2H)-acetic Acid;
3-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}propanenitrile;
10-[2-(3-methylphenoxy)ethyl]-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine-2,4-dione;および
[(2R,3S,4S)-5-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl]dihydrogen phosphate - 前記癌は、肝癌、乳癌、血液癌、子宮頸癌、および前立腺癌よりなる群から選ばれる1種以上であることを特徴とする請求項1に記載の薬学的組成物。
- 前記化合物は、PLK1(polo-like kinase 1)のPBD(polo-box domain)に結合することを特徴とする請求項1に記載の薬学的組成物。
- 前記薬学的組成物は、癌細胞の成長を阻害することを特徴とする請求項1に記載の薬学的組成物。
- 前記薬学的組成物は、癌細胞の細胞死(apoptosis)を誘導することを特徴とする請求項1に記載の薬学的組成物。
- 下記化学式1または2で表示される化合物またはその薬学的に許容可能な塩を有効成分として含む、癌の改善用健康機能食品組成物。
R1は、H、アルキル、または-CnH2nCOOH(nは1~4の整数)であり、
R2は、H、アルキル、-CmH2mCN、-CmH2mOR5、または-CpH2p(CH(OH))qR6であり、R5は、1つ以上のC1-3のアルキルで置換されたフェニルであり、R6は、H、アルキルまたは-OPH2O3であり、mは、2~4の整数であり、pは、1~3の整数であり、qは、2~4の整数であり、
R3は、H、ハロゲン、-NH2、アルキル、または-CH=Oであり、
R4は、H、アルキル、-COOH、または-CX3であり、Xは、ハロゲンである。 - 前記化学式1または2で表示される化合物は、下記化合物よりなる群から選ばれることを特徴とする請求項8に記載の健康機能食品組成物:
2,4-Dioxo-1,2,3,4-tetrahydrobenzo[g]pteridine-7-carboxylic acid;
10-methyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-chloro-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
10-methyl-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
8-amino-1,3-dimethyl-1H,2H,3H,4H-benzo[g]pteridine-2,4-dione;
8-amino-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8,10-trimethyl-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,10-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridine-8-carbaldehyde;
4,10-Dihydro-7,8,10-trimethyl-2,4-dioxobenzo[g]pteridine-3(2H)-acetic Acid;
3-{7,8-dimethyl-2,4-dioxo-2H,3H,4H,10H-benzo[g]pteridin-10-yl}propanenitrile;
10-[2-(3-methylphenoxy)ethyl]-7-(trifluoromethyl)-2H,3H,4H,10H-benzo[g]pteridine-2,4-dione;
7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine-2,4-dione;および
[(2R,3S,4S)-5-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-2,3,4-trihydroxypentyl]dihydrogen phosphate - 下記化学式1または2で表示される化合物またはその薬学的に許容可能な塩を有効成分として含む薬学的組成物を個体に投与する段階を含む、癌の予防または治療方法。
R1は、H、アルキル、または-CnH2nCOOH(nは1~4の整数)であり、
R2は、H、アルキル、-CmH2mCN、-CmH2mOR5、または-CpH2p(CH(OH))qR6であり、R5は、1つ以上のC1-3のアルキルで置換されたフェニルであり、R6は、H、アルキルまたは-OPH2O3であり、mは、2~4の整数であり、pは、1~3の整数であり、qは、2~4の整数であり、
R3は、H、ハロゲン、-NH2、アルキル、または-CH=Oであり、
R4は、H、アルキル、-COOH、または-CX3であり、Xは、ハロゲンである。 - 下記化学式1または2で表示される化合物またはその薬学的に許容可能な塩を有効成分として含む薬学的組成物の、癌の予防または治療用途。
R1は、H、アルキル、または-CnH2nCOOH(nは1~4の整数)であり、
R2は、H、アルキル、-CmH2mCN、-CmH2mOR5、または-CpH2p(CH(OH))qR6であり、R5は、1つ以上のC1-3のアルキルで置換されたフェニルであり、R6は、H、アルキルまたは-OPH2O3であり、mは、2~4の整数であり、pは、1~3の整数であり、qは、2~4の整数であり、
R3は、H、ハロゲン、-NH2、アルキル、または-CH=Oであり、
R4は、H、アルキル、-COOH、または-CX3であり、Xは、ハロゲンである。
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KR10-2018-0149112 | 2018-11-28 | ||
PCT/KR2018/014944 WO2020111325A1 (ko) | 2018-11-28 | 2018-11-29 | Plk1의 활성 억제제를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 |
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WO2014071358A2 (en) * | 2012-11-05 | 2014-05-08 | Foundation Medicine, Inc. | Novel ntrk1 fusion molecules and uses thereof |
CN107468694A (zh) * | 2017-08-03 | 2017-12-15 | 中国科学院成都生物研究所 | 核黄素及其衍生物作为癌症治疗靶向药物及其应用 |
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Non-Patent Citations (1)
Title |
---|
ビタミン, vol. 69, no. 12, JPN6022021677, 1995, pages 707 - 714, ISSN: 0004891635 * |
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