Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor
文献类型：期刊论文
| 作者 | Zhao, Yujun1,2,3,4,5 ; Zhou, Bing1,2,3,4,5; Bai, Longchuan2,3,4,5; Liu, Liu2,3,4,5; Yang, Chao-Yie2,3,4,5; Meagher, Jennifer L.6,7; Stuckey, Jeanne A.6,7; McEachern, Donna2,3,4,5; Przybranowski, Sally2,3,4,5; Wang, Mi2,3,4,5
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2018-07-26 |
| 卷号 | 61期号:14页码:6110-6120 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.8b00483 |
| 文献子类 | Article |
| 英文摘要 | We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NHpyrazole group into the 9H-pyrimido[4,5-b] indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K-i values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in0 both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development. |
| WOS关键词 | TRANSCRIPTIONAL REGULATORS ; FAMILY ; IDENTIFICATION ; ACETYLATION ; CANDIDATE ; CHROMATIN ; RVX-208 ; PROTEIN ; TESTIS ; BRD4 |
| 资助项目 | Prostate Cancer Foundation[00000000] ; OncoFusion Therapeutics, Inc.[00000000] ; University of Michigan Prostate Cancer SPORE grant (NIH/NCI)[P50 CA186786] ; University of Michigan Comprehensive Cancer Core grant (NIH/NCI)[P30CA046592] ; U.S. DOE[DE-AC02-06CH11357] ; Michigan Economic Development Corporation[00000000] ; Michigan Technology Tri-Corridor[085P1000817] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000440521300020 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279651]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Wang, Shaomeng |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Michigan, Coll Pharm, Rogal Canc Ctr, Ann Arbor, MI 48109 USA; 3.Univ Michigan, Coll Pharm, Dept Internal Med, Ann Arbor, MI 48109 USA; 4.Univ Michigan, Coll Pharm, Dept Pharmacol, Ann Arbor, MI 48109 USA; 5.Univ Michigan, Coll Pharm, 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, Dept Biol Chem, Ann Arbor, MI 48109 USA; 8.Univ Michigan, Coll Pharm, Dept Chem, Ann Arbor, MI 48109 USA; 9.Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA; 10.Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA |
| 推荐引用方式 GB/T 7714 | Zhao, Yujun,Zhou, Bing,Bai, Longchuan,et al. Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(14):6110-6120. |
| APA | Zhao, Yujun.,Zhou, Bing.,Bai, Longchuan.,Liu, Liu.,Yang, Chao-Yie.,...&Wang, Shaomeng.(2018).Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor.JOURNAL OF MEDICINAL CHEMISTRY,61(14),6110-6120. |
| MLA | Zhao, Yujun,et al."Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor".JOURNAL OF MEDICINAL CHEMISTRY 61.14(2018):6110-6120. |
入库方式： OAI收割
来源：上海药物研究所
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