CA3020918A1 - Combination therapy with notch and pi3k/mtor inhibitors for use in treating cancer - Google Patents
Combination therapy with notch and pi3k/mtor inhibitors for use in treating cancer Download PDFInfo
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- CA3020918A1 CA3020918A1 CA3020918A CA3020918A CA3020918A1 CA 3020918 A1 CA3020918 A1 CA 3020918A1 CA 3020918 A CA3020918 A CA 3020918A CA 3020918 A CA3020918 A CA 3020918A CA 3020918 A1 CA3020918 A1 CA 3020918A1
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- A—HUMAN NECESSITIES
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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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
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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| TWI609687B (zh) | 2015-04-14 | 2018-01-01 | 美國禮來大藥廠 | 平滑肌肉瘤之標靶性治療 |
| US11564929B2 (en) | 2016-04-12 | 2023-01-31 | Eli Lilly And Company | Combination therapy with Notch and PI3K/mTOR inhibitors for use in treating cancer |
| KR102418765B1 (ko) | 2016-04-12 | 2022-07-08 | 일라이 릴리 앤드 캄파니 | 암 치료를 위한 Notch 및 CDK4/6 억제제의 조합 요법 |
| KR102463617B1 (ko) | 2016-05-20 | 2022-11-03 | 일라이 릴리 앤드 캄파니 | Notch 및 PD-1 또는 PD-L1 억제제를 이용한 조합 요법 |
| EP3525796A1 (en) | 2016-10-12 | 2019-08-21 | Eli Lilly and Company | Targeted treatment of mature t-cell lymphoma |
| KR20190116420A (ko) | 2017-02-17 | 2019-10-14 | 프레드 헛친슨 켄서 리서치 센터 | Bcma 관련 암 및 자가면역 장애의 치료를 위한 조합 요법 |
| TW201932482A (zh) | 2017-11-01 | 2019-08-16 | 美商奇諾治療有限公司 | 對b細胞成熟抗原具特異性之嵌合抗原受體及編碼聚核苷酸 |
| CN111886012A (zh) | 2017-11-06 | 2020-11-03 | 朱诺治疗学股份有限公司 | 细胞疗法与γ分泌酶抑制剂的组合 |
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| ZA9711537B (en) | 1996-12-23 | 1998-06-25 | Athena Neurosciences Inc Eli L | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting ß-amyloid peptide release and/or its synthesis by use of such compounds. |
| JP2002526109A (ja) | 1998-10-02 | 2002-08-20 | ザ ガバメント オブ ザ ユナイテッドステイツ オブ アメリカ アズ リプレゼンテッド バイ ザ セクレタリー デパートメント オブ ヘルス アンド ヒューマン サービシーズ ザ ナショナル インステ | アポトーシス誘導物質と方法 |
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| CN102085372A (zh) * | 2009-12-04 | 2011-06-08 | 中国医学科学院基础医学研究所 | Notch通路抑制剂用于治疗mTOR活化导致的肿瘤的用途 |
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| JO3003B1 (ar) | 2011-01-14 | 2016-09-05 | Lilly Co Eli | مركب أيميدازو [4، 5 -c ] كينولين-2- واحد واستخدامه كمثبط كيناز PI3/mtor |
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| TWI835048B (zh) | 2011-08-01 | 2024-03-11 | 美商建南德克公司 | 利用pd-1軸結合拮抗劑及mek抑制劑治療癌症之方法 |
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| JP6586087B2 (ja) | 2013-08-20 | 2019-10-02 | メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． | Ｐｄ−１アンタゴニストとジナシクリブとの組合せでの癌治療 |
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| MX382902B (es) | 2014-10-31 | 2025-03-13 | Oncomed Pharm Inc | Inhibidor de la vía noth en combinación con un agente inmunoterapéutico para usarse en el tratamiento de cáncer. |
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| EP3662909A1 (en) | 2015-07-24 | 2020-06-10 | Oncotracker, Inc. | Gamma secretase modulators for the treatment of immune system dysfunction |
| KR102418765B1 (ko) * | 2016-04-12 | 2022-07-08 | 일라이 릴리 앤드 캄파니 | 암 치료를 위한 Notch 및 CDK4/6 억제제의 조합 요법 |
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| CN116473978A (zh) | 2016-08-31 | 2023-07-25 | 伊莱利利公司 | 用于治疗实体瘤的给药方案 |
| EP3525796A1 (en) | 2016-10-12 | 2019-08-21 | Eli Lilly and Company | Targeted treatment of mature t-cell lymphoma |
| WO2018201056A1 (en) | 2017-04-28 | 2018-11-01 | Novartis Ag | Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor |
| CN111886012A (zh) | 2017-11-06 | 2020-11-03 | 朱诺治疗学股份有限公司 | 细胞疗法与γ分泌酶抑制剂的组合 |
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