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

Zhao, Yujun; Bai, Longchuan; Liu, Liu; McEachern, Donna; Stuckey, Jeanne A.; Meagher, Jennifer L.; Yang, Chao-Yie; Ran, Xu; Zhou, Bing; Hu, Yang; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Li, Siwei; Sun, Duxin; Wang, Shaomeng

doi:10.1021/acs.jmedchem.7b00193

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

Journal Article · Tue May 02 00:00:00 EDT 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b00193· OSTI ID:1373777

Zhao, Yujun ^[1]; Bai, Longchuan ^[2]; Liu, Liu ^[2]; McEachern, Donna ^[2]; Stuckey, Jeanne A. ^[2]; Meagher, Jennifer L. ^[2];

^[2]; Ran, Xu ^[3];

^[1]; Hu, Yang ^[2]; Li, Xiaoqin ^[2]; Wen, Bo ^[2]; Zhao, Ting ^[2]; Li, Siwei ^[2]; Sun, Duxin ^[2];

^[2]

Univ. of Michigan, Ann Arbor, MI (United States); Chinese Academy of Sciences, Shanghai (China)
Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Michigan, Ann Arbor, MI (United States); Univ. of California, San Francisco, CA (United States)

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. Here, our data show that 31 is a potent, selective, and orally active BET inhibitor.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Inst. of Health; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-06CH11357; P30CA046592; P50 CA186786; 085P1000817

OSTI ID:: 1373777

Journal Information:: Journal of Medicinal Chemistry, Vol. 60, Issue 9; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 34 works

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
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inhibitors
nuclear magnetic resonance spectroscopy
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Title: Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9 H -pyrimido[4,5- b ]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

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