JP5655213B2 - K−Ras突然変異性癌疾患治療剤のスクリーニング方法 - Google Patents
K−Ras突然変異性癌疾患治療剤のスクリーニング方法 Download PDFInfo
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- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
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- 239000012737 fresh medium Substances 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 235000019860 lauric fat Nutrition 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 1
- 235000007708 morin Nutrition 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 230000010807 negative regulation of binding Effects 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- FJDUDHYHRVPMJZ-UHFFFAOYSA-N nonan-1-amine Chemical compound CCCCCCCCCN FJDUDHYHRVPMJZ-UHFFFAOYSA-N 0.000 description 1
- ZVEZMVFBMOOHAT-UHFFFAOYSA-N nonane-1-thiol Chemical compound CCCCCCCCCS ZVEZMVFBMOOHAT-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- KZCOBXFFBQJQHH-UHFFFAOYSA-N octane-1-thiol Chemical compound CCCCCCCCS KZCOBXFFBQJQHH-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- CBXWGGFGZDVPNV-UHFFFAOYSA-N so4-so4 Chemical compound OS(O)(=O)=O.OS(O)(=O)=O CBXWGGFGZDVPNV-UHFFFAOYSA-N 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 108091008023 transcriptional regulators Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 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
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/5748—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving oncogenic proteins
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
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- Epidemiology (AREA)
- Urology & Nephrology (AREA)
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- Hematology (AREA)
- Biomedical Technology (AREA)
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- Analytical Chemistry (AREA)
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- General Physics & Mathematics (AREA)
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
mは、0ないし10の整数、n及びpは、それぞれ0または1の整数であり、
Zは、−NH(CH2)qCH3、−OH、4−フェニルピペリジン基、4−フェニル
ピペラジン基、イソブチルアミノ基及びイソブチルオキシ基からなる群から選択され、
qは、0ないし9の整数である。
1,5−ジヒドロキシナフタレン(2)を出発物質として用いて、既に知られた3段階の反応を経て、1,4,5,8−テトラメトキシナフタレン(3)を合成し、再び脱メチル化して合成中間体である5,8−ジメトキシ−1,4−ナフトキノン(4)を合成した。詳しい合成方法は、合成スキームにある参考文献で見られるが、このとき使われた溶媒は、反応に悪影響を及ぼさない溶媒である水酸化ナトリウム、アセトニトリル、無水メタノール、N,N−ジメチルホルムアミド、クロロホルムなどを使った。初めのメチル化反応は、窒素ガス存在下で水酸化ナトリウムに溶かした1,5−ジヒドロキシナフタレンに硫酸ジメチルを1時間滴加して2時間反応させて得た。後でベンゼンで再結晶して1,5−ジメトキシナフタレンを得た。
[スネイル媒介p53抑制に関する分子的機転の考察]
<実施例1>
6ヶ月齢の雄マウスを犠牲させて肺線維芽細胞(fibroblast)を集めた。肺を分離した後、組職メスを用いて組職を切って溶出した。20% FBSを含有したDMEM培地で3日間培養した後、付着された細胞を培養皿に分周し、jetPEIを用いて製造者の指針によって突然変異H−Ras、N−Ras及びK−Rasで形質感染させた。72時間後、DMEM含有G418 400μg/mlを用いて形質感染された細胞を選別した。
2.細胞培養及び試薬準備
3.免疫染色及びウェスタンブロット
細胞形質感染のために、製造者のプロトコルによってjetPEIを利用した。細胞を完全培地で24時間DNA/jetPEI混合物で培養した。生体外遺伝子ノックアウトのために、Snail及びMDM2に対するsi−RNAを作った。jetPEIを用いてsi−RNAを形質感染させて24時間後、その効果を検討した。
5.実験結果
<実施例2>
1.ウェスタンブロット及び生体外のキナーゼまたはバインディング分析
2.実験結果
K−Rasが、スネイルを如何に誘導するかを検証するために、AKTの関連を検討した。Rasは、AKTを活性化してGSK−3β媒介スネイル不安定性を抑制できると知られている。
<実施例3>
1.再組合タンパク質及びGST−pull down分析
スネイルは、核タンパク質であるために、スネイル及びp53を共に形質感染させた時、スネイル及びp53がいずれも消えた(図3Dないし図3F参照)。図8Aのように、endo−IPからこれらタンパク質が互いに関連するということが分かった。図8B及び図8Cのように、Far−western blot分析及びGST−pull down分析を通じてスネイル及びp53が互いに直接的に相互作用するというが分かった。また、p53のDNA結合ドメイン及びスネイルの中間領域が、結合ドメインとして役割を行った(図8Dないし図8F、図6E、図6F参照)。
<実施例4>
1.化学的スクリーニングのためのELISAシステムの製造
2.実験結果
[p53のDNA結合ドメインのエンドサイトーシスを利用したK−Ras突然変異細胞の特異的に薬物伝達方法の考察]
<実施例5>
GST−pull down分析のために、先ず人間スネイル及びp53再組合タンパク質を知られた方法によって製造した(Neoplasia 11:1−10,2009)。培地及び前細胞ライセートでp53及びスネイル間の直接的な結合を検討するために、アガロース−ビーズ接合GSTまたはGST−スネイルを細胞ライセートまたは培養培地と4℃で2時間培養した。PBS及びRIPAで洗浄後、沈降されたタンパク質を以前方法と同様にSDS−PAGE及びWBに適用した。
2.実験結果
<実施例6>
1.細胞外p53及びスネイルの態様検討
正常及び腫瘍が一対を成す胆管癌及び肝組職を順天郷医薬センターから得た。組職をdeep freezerで素早く凍結し、該凍結された組職を切って0.5mgの組職を0.25mL血清フリー培地で37℃で30分間培養して組職液を遊離した。培養後、培養培地を集めて0.5mL 100% EtOHで沈降させた。該沈降された物質をRIPAを用いて溶解させ、以前方法と同様にSDS−PAGE及びWB分析を行った。また、同じ方法で同一培養培地を得てp53 Abを検出した。
p53の調査のために、製造者の指針(Assay Design)によってELISAを行った。すなわち、0.2mL組職培養培地を各ウェルに加えて検出Abと培養した。洗浄緩衝液で洗浄した後、0.2mL基質ゾル及び0.05mL停止液を加えた。
人間血液試料を順天郷大学(膵膓癌及び胆石患者)から得て、釜山大学の医薬センター(肺癌)から得た。正常血液試料を志願者または癌ではない患者から集めた。血清は遠心分離して集め、使用前まで−70℃で保管された。3μlの血清をGST−タンパク質と事前承認後、アガロース−接合GST−スネイル−Nと培養した。沈降されたGST−スネイル−Ab複合体は、RIPA及びSDS試料緩衝液で溶解し、以前方法と同様にSDS−PAGEに適用した。PVDF膜に移した後、タンパク質を抗−人間Ab及び抗−GST Abと培養した。
2.実験結果
<実施例1>
1−1.2−メチルチオ−1,4−ナフトキノン(2−Methylthio−1,4−naphthoquinone、1a)の合成
1−2.2−エチルチオ−1,4−ナフトキノン(2−Ethylthio−1,4−naphthoquinone、1b)の合成
1−3.2−プロピルチオ−1,4−ナフトキノン(2−Propylthylthio−1,4−naphthoquinone、1c)の合成
1−4.2−ブチルチオ−1,4−ナフトキノン(2−Butylthio−1,4−naphthoquinone、1d)の合成
1−5.2−ペンチルチオ−1,4−ナフトキノン(2−Pentylthio−1,4−naphthoquinone、1e)の合成
1−6.2−ヘキシルチオ−1,4−ナフトキノン(2−Hexylthio−1,4−naphthoquinone、1e)の合成
1−7.2−ヘプチルチオ−1,4−ナフトキノン(2−Heptylthio−1,4−naphthoquinone、1g)の合成
1−8.2−オクチルチオ−1,4−ナフトキノン(2−Octylthio−1,4−naphthoquinone、1h)の合成
1−9.2−ノニルチオ−1,4−ナフトキノン(2−Nonylthio−1,4−naphthoquinone、1i)の合成
1−10.2−デシルチオ−1,4−ナフトキノン(2−Decylthio−1,4−naphthoquinone、1j)の合成
<実施例2>
2−1.2−メチルアミノ−5,8−ジメトキシ−1.4−ナフトキノン(2−Methylamino−5,8− dimethoxy−1,4 −naphthoquinone、5a)の合成
2−2.2−エチルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Ethylamino−5,8−dimethoxy−1,4−naphthoquinone、5b)の合成
2−3.2−プロピルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Propylamino−5,8−dimethoxy−1,4−naphthoquinone、5c)の合成
2−4.2−ブチルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Butylamino−5,8−dimethoxy−1,4−naphthoquinone、5d)の合成
2−5.2−ペンチルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Pentylamino−5,8−dimethoxy−1,4−naphthoquinone、5e)の合成
2−6.2−ヘキシルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Hexylamino−5,8−dimethoxy−1,4−naphthoquinone、5f)の合成
2−7.2−ヘブチルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Heptylamino−5,8− dimethoxy−1,4−naphthoquinone、5g)の合成
2−8.2−オクチルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Octylamino−5,8−dimethoxy−1,4−naphthoquinone、5h)の合成
2−9.2−ノニルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Nonylamino−5,8−dimethoxy−1,4−naphthoquinone、5i)の合成
2−10.2−デシルアミノ−5,8−ジメトキシ−1,4−ナフトキノン(2−Decylamino−5,8−dimethoxy−1,4−naphthoquinone、5j)の合成
2−11.2−(2−ヒドロキシエチルチオ)−5,8−ジメトキシ−1,4−ナフトキノン[2−(2−Hydroxyethylthio)−5,8−dimethoxy−1,4−naphthoquinone、5k]の合成
2−12.2−(3−ヒドロキシプロピルチオ)−5,8−ジメトキシ−1,4−ナフトキノン[2−(3−Hydroxypropylthio)−5,8−dimethoxy−1,4−naphthoquinone、5l]の合成
2−13.2−(4−ヒドロキシブチルチオ)−5,8−ジメトキシ−1,4−ナフトキノン[2−(4−Hydroxybutylthio)−5,8−dimethoxy−1,4−naphthoquinone、5m]の合成
2−14.2−(6−ヒドロキシヘキシルチオ)−5,8−ジメトキシ−1,4−ナフトキノン[2−(6−Hydroxyhexylthio)−5,8−dimethoxy−1,4−naphthoquinone、5n]の合成
2−15.3−(5,8−ジメトキシ−1,4−ジオキソナフタレン−2−イルチオ)プロパン酸[3−(5,8−dimethoxy−1,4−dioxo−naphthalen−2−ylthio)propanoic acid、5o]の合成
2−16.11−(5,8−ジメトキシ−1,4−ジオキソ−ナフタレン−2−イルチオ)ウンデカン酸[11−(5,8−dimethoxy−1,4−dioxo−naphthalen−2−ylthio)undecanoic acid、5p]の合成
<実施例3>
3−1.5,8−ジメトキシ−2−[3−オキソ−3−(4−フェニルピペリジン−4−イル)プロピルチオ]−1,4−ナフトキノン[5,8−dimethoxy−2−(3−oxo−3−(4−phenylpiperazin−1−yl)propylthio)naphthalene−1,4−dione、6a]の合成
<実施例4>
4−1.イソブチル−11−(5,8−ジメトキシ−1,4−ジオキソ−1,4−ジヒドロナフタレン−2−イルチオ)−ウンデカノアート[Isobutyl−11−(5,8−dimethoxy−1,4−dioxo−1,4−dihydronaphthalene−2−ylthio)undecanoate、7a]の合成
4−2.11−(5,8−ジメトキシ−1,4−ジオキソ−1,4−ジヒドロナフタレン−2−イルチオ)−N−イソブチルウンデカンアミド[11−(5,8−dimethoxy−1,4−dioxo−1,4−dihydronaphthalene−2−ylthio)−N−isobutyl undecanamide、7b]の合成
<実施例5>
5−1.イソブチル11−(5,8−ジメトキシ−1,4−ジオキソ−1,4−ジヒドロナフタレン−2−イルスルフィニル)ウンデカノアート[isobutyl11−(5,8−dimethoxyl−1,4−dioxo−1,4−dihydronaphthalene−2−yl sulfinyl)undecanoate、8]の合成
<実験例1>p53活性回復及びターゲット遺伝子誘導確認
<実験例2>スネイル−p53結合阻害効果の確認
<実験例3>K−Ras依存的なp53誘導能の確認
<実験例4>p53のターゲット遺伝子の活性誘導
前記化合物5oを突然変異p53類型であるMT/WT−p53遺伝子を有するMDA−MB 468という人間乳房癌細胞株に処理してウェスタンブロットを実施した。図23は、MDA−MBに5oを処理して実施したウェスタンブロットの結果を表わすグラフであり、表5は、このグラフ値を数値で表わした図表である。
<実験例5>生体内異種移植(xenograft)の考察
非胸腺マウスをDaehan Biolink Co.Ltdから購入し、温度及び光の調節条件(20−23℃、12時間光/12時間暗周期)下で生育させ、滅菌食餌と水とを自在に供給した。2週後、非胸腺マウス(n=21)に腹腔注射を通じてA549細胞を1X107細胞で接種した。2週後、各グループを3つのサブグループに分けてPBS、10mg/kgまたは20mg/kgの5oを一週間に一回ずつ10週間腹腔内に投与し、生存率を観察した。動物試験は、釜山大学校動物保護委員会の承認及び指針によって行われた。
図24のように、10mg/kgと20mg/kgとの5oの処理によって腫瘍による死亡率が遮断された一方、PBS処理群では、10週後に生存率が50%以下になり、図25に示したように、5o処理群での腫瘍は、ほとんど死滅する形状が観察された。また、図26のように、体重減少や化合物注射による総体的な解剖学的異常所見を観察することができなかった。下記表6は、腫瘍の発生位置及び形態学的特徴を要約したものである。
配列番号1は、人間p53細胞性腫瘍抗原のアミノ酸配列を表わしたものである。
Claims (1)
- p53を固定させたプレートにスネイル及び候補薬物を培養する段階と、
ELISAリーダーでスネイル−p53の結合を阻害する候補薬物を選別する段階と、
を含んでなることを特徴とするK−Ras突然変異性癌疾患治療剤のスクリーニング方法。
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KR10-2009-0018956 | 2009-03-05 | ||
KR10-2009-0075529 | 2009-08-17 | ||
KR20090075529 | 2009-08-17 | ||
KR10-2009-0111710 | 2009-11-18 | ||
KR1020090111710A KR101298168B1 (ko) | 2008-11-21 | 2009-11-18 | 스네일―p53 간의 결합을 저해하는 화합물 및 이를 유효성분으로 함유하는 암질환 치료제 |
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JP2014004513A Active JP5655213B2 (ja) | 2008-11-21 | 2014-01-14 | K−Ras突然変異性癌疾患治療剤のスクリーニング方法 |
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WO2008095063A1 (en) | 2007-01-31 | 2008-08-07 | Dana-Farber Cancer Institute, Inc. | Stabilized p53 peptides and uses thereof |
EP2508531B1 (en) | 2007-03-28 | 2016-10-19 | President and Fellows of Harvard College | Stitched polypeptides |
SI2603600T1 (sl) | 2010-08-13 | 2019-04-30 | Aileron Therapeutics, Inc. | Peptidomimetični makrocikli |
AU2012326026B2 (en) | 2011-10-18 | 2017-04-13 | Aileron Therapeutics, Inc. | Peptidomimetic macrocyles |
WO2013123267A1 (en) | 2012-02-15 | 2013-08-22 | Aileron Therapeutics, Inc. | Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles |
CN112500466B (zh) | 2012-02-15 | 2022-05-03 | 艾瑞朗医疗公司 | 拟肽大环化合物 |
AU2013337388B2 (en) | 2012-11-01 | 2018-08-02 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
US9910833B2 (en) | 2012-11-13 | 2018-03-06 | International Business Machines Corporation | Automatically rendering web and/or hybrid applications natively in parallel |
BR112017005598A2 (pt) | 2014-09-24 | 2017-12-12 | Aileron Therapeutics Inc | macrociclos peptidomiméticos e usos dos mesmos |
SG10201902598VA (en) | 2014-09-24 | 2019-04-29 | Aileron Therapeutics Inc | Peptidomimetic macrocycles and formulations thereof |
KR20170129879A (ko) | 2015-03-20 | 2017-11-27 | 에일러론 테라퓨틱스 인코포레이티드 | 펩티드모방 거대고리 및 이의 용도 |
EP3347372A4 (en) | 2015-09-10 | 2019-09-04 | Aileron Therapeutics, Inc. | PEPTIDOMIMETIC MACROCYCLES AS MODULATORS OF MCL-1 |
CN105646300B (zh) * | 2016-01-25 | 2017-11-10 | 黑龙江八一农垦大学 | 一种2‑辛亚砜‑1,4‑萘醌的制备方法 |
CN105541679B (zh) * | 2016-01-25 | 2017-05-31 | 黑龙江八一农垦大学 | 一种2‑辛亚砜‑1,4‑萘醌化合物 |
CN105541676B (zh) * | 2016-01-25 | 2017-08-04 | 黑龙江八一农垦大学 | 一种2‑丁亚砜‑1,4‑萘醌化合物 |
CN107496394B (zh) * | 2017-09-27 | 2019-01-04 | 武汉迈特维尔生物科技有限公司 | 一种miR-21基因抑制剂及用于治疗宫颈癌的用途 |
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