JP2015527316A - 併用療法iii - Google Patents
併用療法iii Download PDFInfo
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- JP2015527316A JP2015527316A JP2015521033A JP2015521033A JP2015527316A JP 2015527316 A JP2015527316 A JP 2015527316A JP 2015521033 A JP2015521033 A JP 2015521033A JP 2015521033 A JP2015521033 A JP 2015521033A JP 2015527316 A JP2015527316 A JP 2015527316A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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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
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
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- C12Y—ENZYMES
- C12Y305/00—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5)
- C12Y305/01—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in linear amides (3.5.1)
- C12Y305/01098—Histone deacetylase (3.5.1.98), i.e. sirtuin deacetylase
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Abstract
Description
(式中、
R’は、H又はアルキルであり;
R’’は、H又はアルコキシであり;
R1及びR2は、Hであるか、又は一緒にオキソを形成し;
R3及びR4は、独立してH若しくはOHであるか、又は一緒にオキソを形成し;
R5、R6、R6’、R7、及びR8は、H、アルキル、アルコキシ、ヒドロキシ、ヒドロキシルアルキル、アルコキシカルボニル、モノアルキルアミノ及びジアルキルアミノからなる群から独立して選択され;
Xは、CH2又はOであり;
nは、0又は1である)
を有する。
からなる群から選択される。
(式中、
R’は、H又はアルキルであり;
R’’は、H又はアルコキシであり;
R1及びR2は、Hであるか、又は一緒にオキソを形成し;
R3及びR4は、独立してH若しくはOHであるか、又は一緒にオキソを形成し;
R5、R6、R6’、R7、及びR8は、独立して、H、アルキル、アルコキシ、ヒドロキシ、ヒドロキシルアルキル、アルコキシカルボニル、モノアルキルアミノ及びジアルキルアミノからなる群から選択され;
Xは、CH2又はOであり;
nは、0又は1である)を有する。
真核生物の細胞培養及び小分子干渉RNA(siRNA)のトランスフェクション:本試験のために、T98Gヒトグリア芽細胞腫細胞系を使用した。37℃、5%CO2の加湿雰囲気内で、10%熱不活性化FCS及びペニシリン(100単位/mL)−ストレプトマイシン(100Ag/mL)を加えたイーグル(Eagle)のMEM(Sigma−Aldrich)で細胞を培養した。製造業者の使用説明書に従って、リポフェクトアミン(Lipofectamine)RNAiMAX試薬(Invitrogen)を用いて、小分子干渉RNA(siRNA又はdsRNA)トランスフェクションを実施した。トランスフェクションは、フォワードトランスフェクションプロトコルを用いて実施した。以下のsiRNA配列を使用した:スクランブルされた(5’−GUA ACA AUG AGA GCA CGG C−3’;配列番号171)、HDAC4(5’−UCA UAC ACG AGG CCU GUC GUU−3’;配列番号2)、HDAC4.2(5’−AAA UUA CGG UCC AGG CUA AUU−3’;配列番号5)。
がん細胞の生存及び異なる化学薬剤への感受性に及ぼすHDAC4阻害の影響を研究するために、まずは、ヒトグリア芽細胞腫T98G細胞を、スクランブルsiRNA(配列番号171に表される非標的siRNA)又はHDAC4特異的siRNA(配列番号2に表される)で72時間、一時的にトランスフェクトさせた。HDAC4特異的siRNAによる有効なタンパク質の下方制御を、免疫ブロット法によって示した(図1A)。
Claims (13)
- 医薬として用いるための、少なくとも1種類のHDAC4サイレンシング剤と、式(I):
(式中、
R’は、H又はアルキルであり;
R’’は、H又はアルコキシであり;
R1及びR2は、Hであるか、又は一緒にオキソを形成し;
R3及びR4は、独立してH若しくはOHであるか、又は一緒にオキソを形成し;
R5、R6、R6’、R7、及びR8は、独立して、H、アルキル、アルコキシ、ヒドロキシ、ヒドロキシルアルキル、アルコキシカルボニル、モノアルキルアミノ及びジアルキルアミノからなる群から選択され;
Xは、CH2又はOであり;
nは、0又は1である)
の化合物との組合せ。 - 前記HDAC4サイレンシング剤が、siRNA分子、DsiRNA分子、人工miRNA前駆体、shRNA分子、アンチセンスオリゴヌクレオチド、及びリボザイムからなる群から選択される、請求項1に記載の組合せ。
- 前記HDAC4サイレンシング剤が、配列番号1から170からなる群から選択される核酸配列を含む、請求項1に記載の組合せ。
- 式(I)の前記化合物が、
からなる群から選択される、請求項1に記載の組合せ。 - 脳がん、神経膠腫、星状細胞腫、及びグリア芽細胞腫からなる群から選択される過剰増殖性疾患の処置で用いるための、請求項1に記載の組合せ。
- 前記HDAC4サイレンシング剤及び式(I)の前記化合物が、同時に、逐次に、又は別々に投与される、請求項1から5までのいずれか一項に記載の組合せ。
- 請求項1から6までのいずれか一項に記載の組合せ、及び少なくとも1つの薬学的に許容される担体を含む医薬組成物。
- 過剰増殖性細胞を化学療法剤に対して感作させる方法であって、そのような感作を必要とするヒト又は動物対象においてHDAC4遺伝子をサイレンシングすることによって感作させる方法。
- 過剰増殖性疾患を処置する方法であって、そのような処置を必要とするヒト又は動物対象において、少なくとも1種類のHDAC4サイレンシング剤及び式(I):
(式中、
R’は、H又はアルキルであり;
R’’は、H又はアルコキシであり;
R1及びR2は、Hであるか、又は一緒にオキソを形成し;
R3及びR4は、独立してH、OHであるか、又は一緒にオキソを形成し;
R5、R6、R6’、R7、及びR8は、独立して、H、アルキル、アルコキシ、ヒドロキシ、ヒドロキシルアルキル、アルコキシカルボニル、モノアルキルアミノ及びジアルキルアミノからなる群から選択され;
Xは、CH2又はOであり;
nは、0又は1である)
の化合物を、併用して、同時に、又は逐次に該対象に投与することによる、上記方法。 - 前記HDAC4サイレンシング剤が、siRNA分子、DsiRNA分子、人工miRNA前駆体、shRNA分子、アンチセンスオリゴヌクレオチド、及びリボザイムからなる群から選択される、請求項8又は9に記載の方法。
- 前記HDAC4サイレンシング剤が、配列番号1から170からなる群から選択される核酸配列を含む、請求項8又は9に記載の方法。
- 脳がん、神経膠腫、星状細胞腫、及びグリア芽細胞腫からなる群から選択される過剰増殖性疾患の処置のための、請求項8又は9に記載の方法。
- 前記HDAC4サイレンシング剤及び式(I)の前記化合物が、同時に、逐次に、又は別々に投与される、請求項8から12までのいずれか一項に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI20125795 | 2012-07-13 | ||
FI20125795 | 2012-07-13 | ||
PCT/FI2013/050745 WO2014009609A1 (en) | 2012-07-13 | 2013-07-11 | Combination therapy iii |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2015527316A true JP2015527316A (ja) | 2015-09-17 |
JP2015527316A5 JP2015527316A5 (ja) | 2016-09-01 |
JP6393682B2 JP6393682B2 (ja) | 2018-09-19 |
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Application Number | Title | Priority Date | Filing Date |
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JP2015521033A Expired - Fee Related JP6393682B2 (ja) | 2012-07-13 | 2013-07-11 | 併用療法iii |
Country Status (8)
Country | Link |
---|---|
US (1) | US10166241B2 (ja) |
EP (1) | EP2872631B1 (ja) |
JP (1) | JP6393682B2 (ja) |
CN (1) | CN104619845A (ja) |
CA (1) | CA2878873C (ja) |
DK (1) | DK2872631T3 (ja) |
ES (1) | ES2627500T3 (ja) |
WO (1) | WO2014009609A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106344923B (zh) * | 2016-09-23 | 2019-09-27 | 中国人民解放军第二军医大学第二附属医院 | 组蛋白去乙酰化酶-4抑制剂在制备治疗多发性骨髓瘤疾病药物中的应用 |
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US20040077083A1 (en) * | 2002-10-17 | 2004-04-22 | Isis Pharmaceuticals Inc. | Antisense modulation of histone deacetylase 4 expression |
JP2007501774A (ja) * | 2003-08-08 | 2007-02-01 | ノバルティス アクチエンゲゼルシャフト | スタウロスポリンを含む組み合わせ |
JP2009541240A (ja) * | 2006-06-23 | 2009-11-26 | ノバルティス アクチエンゲゼルシャフト | スタウロスポリンを含む組み合わせ |
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2013
- 2013-07-11 JP JP2015521033A patent/JP6393682B2/ja not_active Expired - Fee Related
- 2013-07-11 ES ES13745446.8T patent/ES2627500T3/es active Active
- 2013-07-11 CA CA2878873A patent/CA2878873C/en not_active Expired - Fee Related
- 2013-07-11 EP EP13745446.8A patent/EP2872631B1/en not_active Not-in-force
- 2013-07-11 WO PCT/FI2013/050745 patent/WO2014009609A1/en active Application Filing
- 2013-07-11 CN CN201380047501.9A patent/CN104619845A/zh active Pending
- 2013-07-11 DK DK13745446.8T patent/DK2872631T3/en active
- 2013-07-11 US US14/414,393 patent/US10166241B2/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2002526450A (ja) * | 1998-09-18 | 2002-08-20 | スミスクライン・ビーチャム・コーポレイション | Chk1キナーゼ阻害物質 |
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US20150209369A1 (en) | 2015-07-30 |
DK2872631T3 (en) | 2017-06-12 |
EP2872631A1 (en) | 2015-05-20 |
US10166241B2 (en) | 2019-01-01 |
CA2878873C (en) | 2018-08-21 |
EP2872631B1 (en) | 2017-05-03 |
JP6393682B2 (ja) | 2018-09-19 |
ES2627500T3 (es) | 2017-07-28 |
CA2878873A1 (en) | 2014-01-16 |
CN104619845A (zh) | 2015-05-13 |
WO2014009609A1 (en) | 2014-01-16 |
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