JP2010533478A - ガンマセクレターゼの阻害剤の基質特異性を同定するための組成物および方法 - Google Patents
ガンマセクレターゼの阻害剤の基質特異性を同定するための組成物および方法 Download PDFInfo
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- JP2010533478A JP2010533478A JP2010516305A JP2010516305A JP2010533478A JP 2010533478 A JP2010533478 A JP 2010533478A JP 2010516305 A JP2010516305 A JP 2010516305A JP 2010516305 A JP2010516305 A JP 2010516305A JP 2010533478 A JP2010533478 A JP 2010533478A
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| EP2177623A4 (en) * | 2007-07-19 | 2010-12-29 | Eisai R&D Man Co Ltd | SCREENING METHOD USING C-MET, A NEW SUBSTRATE FOR GAMMA SECRETASE |
| WO2009017234A1 (ja) * | 2007-08-01 | 2009-02-05 | Eisai R & D Management Co., Ltd. | γ-セクレターゼの新規基質c-Retを利用したスクリーニング方法 |
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| US8530181B2 (en) * | 2007-11-15 | 2013-09-10 | Eisai R&D Management Co., Ltd. | Method of screening for compounds which affect the cleavage of EphA7 byγ-secretase |
| US7892769B2 (en) * | 2007-11-30 | 2011-02-22 | Eisai R&D Management Co., Ltd. | Processing of EphA4 polypeptide by γ-secretase activity |
| WO2012081502A1 (ja) | 2010-12-17 | 2012-06-21 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ゼラチナーゼによるEphA4の切断反応を指標としたスクリーニング方法 |
| WO2012147798A1 (ja) | 2011-04-25 | 2012-11-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | EphA4細胞外ドメインの測定による認知機能障害を伴う神経系疾患の検出方法 |
| CN110079580B (zh) | 2012-06-22 | 2022-12-06 | 真蒂奥姆责任有限公司 | 用于测定去纤维蛋白多核苷酸的生物活性的基于优球蛋白的方法 |
| EP3759127A4 (en) * | 2018-03-02 | 2022-03-30 | Ionis Pharmaceuticals, Inc. | COMPOUNDS AND METHODS FOR MODULATING AMYLOID BETA PRECURSOR PROTEIN |
| MA56466A (fr) | 2019-07-01 | 2022-05-11 | Eisai R&D Man Co Ltd | Anticorps anti-epha4 |
| US11913964B2 (en) | 2020-02-27 | 2024-02-27 | Adeptrix Corp. | Multiplexed bead-based analytical assays |
| US20230174612A1 (en) * | 2020-04-09 | 2023-06-08 | The Regents Of The University Of California | Notch receptors with zinc finger-containing transcriptional effector |
| UY39344A (es) | 2020-07-28 | 2022-02-25 | Ionis Pharmaceuticals Inc | Compuestos y métodos para reducir la expresión de app |
Family Cites Families (8)
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| US5441870A (en) * | 1992-04-15 | 1995-08-15 | Athena Neurosciences, Inc. | Methods for monitoring cellular processing of β-amyloid precursor protein |
| US5604102A (en) * | 1992-04-15 | 1997-02-18 | Athena Neurosciences, Inc. | Methods of screening for β-amyloid peptide production inhibitors |
| US5766846A (en) * | 1992-07-10 | 1998-06-16 | Athena Neurosciences | Methods of screening for compounds which inhibit soluble β-amyloid peptide production |
| US5605811A (en) | 1992-10-26 | 1997-02-25 | Athena Neurosciences, Inc. | Methods and compositions for monitoring cellular processing of beta-amyloid precursor protein |
| DE69426571T2 (de) | 1993-10-27 | 2001-08-09 | Elan Pharm Inc | TRANSGENE TIERE, DIE APP Allele mit der schwedischen Mutation beherbergen |
| DE10131899A1 (de) * | 2001-07-04 | 2003-02-27 | Boehringer Ingelheim Pharma | In vitro-Screening-Assay für gamma-Secretase |
| WO2007058987A1 (en) * | 2005-11-10 | 2007-05-24 | Bristol-Myers Squibb Company | Methods of identifying compounds that inhibit notch cleavage |
| US20090163594A1 (en) * | 2007-10-31 | 2009-06-25 | Elan Pharmaceuticals, Inc. | Triple Assay System for Identifying Substrate Selectivity of Gamma Secretase Inhibitors |
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- 2008-07-14 JP JP2010516305A patent/JP2010533478A/ja not_active Withdrawn
- 2008-07-14 EP EP08826401A patent/EP2183598A1/en not_active Withdrawn
- 2008-07-14 WO PCT/US2008/070012 patent/WO2009012237A1/en not_active Ceased
- 2008-07-14 US US12/172,978 patent/US20090023158A1/en not_active Abandoned
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2011
- 2011-03-08 US US13/043,278 patent/US20110306071A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020058360A (ja) * | 2014-11-27 | 2020-04-16 | ゲンチウム エス．アール．エル． | デフィブロチドの能力を決定する為の細胞に基づく方法 |
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| US20110306071A1 (en) | 2011-12-15 |
| WO2009012237A1 (en) | 2009-01-22 |
| EP2183598A1 (en) | 2010-05-12 |
| US20090023158A1 (en) | 2009-01-22 |
| CA2692604A1 (en) | 2009-01-22 |
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