Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression
文献类型：期刊论文
| 作者 | Qin, Chong2,3; Hu, Yang2,3; Zhou, Bing2,3,8 ; Fernandez-Salas, Ester1,2; Yang, Chao-Yie2,3; Liu, Liu2,3; McEachern, Donna2,3; Przybranowski, Sally2,3; Wang, Mi2,3; Stuckey, Jeanne
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2018-08-09 |
| 卷号 | 61期号:15页码:6685-6704 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.8b00506 |
| 文献子类 | Article |
| 英文摘要 | Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCAS70 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date. |
| WOS关键词 | RESISTANT PROSTATE-CANCER ; SMALL-MOLECULE PROTACS ; E3 UBIQUITIN LIGASE ; DRUG DISCOVERY ; INHIBITORS ; DEGRADATION ; DESIGN ; STRATEGY ; OPTIMIZATION ; INFLAMMATION |
| 资助项目 | Breast Cancer Research Foundation[00000000] ; Prostate Cancer Foundation[00000000] ; National Cancer Institute, NIH[R01CA215758] ; University of Michigan Comprehensive Cancer Center support grant from the National Cancer Institute, NIH[P30 CA046592] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000441484300015 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279623]  |
| 专题 | 药物化学研究室 |
| 通讯作者 | Wang, Shaomeng |
| 作者单位 | 1.Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA; 2.Univ Michigan, Sch Med, Rogel Canc Ctr, Ann Arbor, MI 48109 USA; 3.Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA; 4.Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA; 5.Univ Michigan, Sch Med, Dept Med Chem, Ann Arbor, MI 48109 USA; 6.Univ Michigan, Coll Pharm, Life Sci Inst, Ann Arbor, MI 48109 USA; 7.Univ Michigan, Coll Pharm, Pharmacokinet Core, Ann Arbor, MI 48109 USA; 8.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Qin, Chong,Hu, Yang,Zhou, Bing,et al. Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(15):6685-6704. |
| APA | Qin, Chong.,Hu, Yang.,Zhou, Bing.,Fernandez-Salas, Ester.,Yang, Chao-Yie.,...&Wang, Shaomeng.(2018).Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression.JOURNAL OF MEDICINAL CHEMISTRY,61(15),6685-6704. |
| MLA | Qin, Chong,et al."Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression".JOURNAL OF MEDICINAL CHEMISTRY 61.15(2018):6685-6704. |
入库方式： OAI收割
来源：上海药物研究所
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