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Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

文献类型：期刊论文

作者Zhao, Yujun1,2,3,4,8; Bai, Longchuan1,2,3,4; Liu, Liu1,2,3,4; McEachern, Donna1,2,3,4; Stuckey, Jeanne A.6,7; Meagher, Jennifer L.6,7; Yang, Chao-Yie1,2,3,4; Ran, Xu1,2,3,4,9; Zhou, Bing1,2,3,4,8; Hu, Yang1,2,3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2017-05-11
卷号60期号:9页码:3887-3901
ISSN号0022-2623
DOI10.1021/acs.jmedchem.7b00193
文献子类Article
英文摘要We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.
WOS关键词PHASE-I TRIAL ; HEMATOLOGIC MALIGNANCIES ; DRUG DISCOVERY ; BREAST-CANCER ; OPTIMIZATION ; DESIGN ; IDENTIFICATION ; KINASE ; OTX015 ; FAMILY
资助项目Prostate Cancer Foundation[00000000] ; OncoFusion Therapeutics[00000000] ; University of Michigan Comprehensive Cancer Core grant (NIH/NCI)[University of Michigan Comprehensive Cancer Core grant (NIH/NCI] ; University of Michigan Comprehensive Cancer Core grant (NIH/NCI)[Grant P30CA046592] ; University of Michigan Prostate Cancer SPORE grant (NIH/NCI)[P50 CA186786] ; 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:000401403100025
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/272665]  
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.Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA;
2.Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA;
3.Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA;
4.Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA;
5.Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA;
6.Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA;
7.Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA;
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
9.Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA
推荐引用方式
GB/T 7714		 Zhao, Yujun,Bai, Longchuan,Liu, Liu,et al. Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(9):3887-3901.
APA Zhao, Yujun.,Bai, Longchuan.,Liu, Liu.,McEachern, Donna.,Stuckey, Jeanne A..,...&Wang, Shaomeng.(2017).Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor.JOURNAL OF MEDICINAL CHEMISTRY,60(9),3887-3901.
MLA Zhao, Yujun,et al."Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor".JOURNAL OF MEDICINAL CHEMISTRY 60.9(2017):3887-3901.

入库方式： OAI收割

来源：上海药物研究所

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