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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

Abstract

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.

Authors:
 [1];  [2];  [2];  [2];  [2];  [2]; ORCiD logo [2];  [3]; ORCiD logo [1];  [2];  [2];  [2];  [2];  [2];  [2]; ORCiD logo [2]
  1. Univ. of Michigan, Ann Arbor, MI (United States); Chinese Academy of Sciences, Shanghai (China)
  2. Univ. of Michigan, Ann Arbor, MI (United States)
  3. Univ. of Michigan, Ann Arbor, MI (United States); Univ. of California, San Francisco, CA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Inst. of Health; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor
OSTI Identifier:
1373777
Grant/Contract Number:  
AC02-06CH11357; P30CA046592; P50 CA186786; 085P1000817
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 60; Journal Issue: 9; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; mixtures; rodent models; inhibitors; nuclear magnetic resonance spectroscopy; screening assays

Citation Formats

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, and Wang, Shaomeng. 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. United States: N. p., 2017. Web. https://doi.org/10.1021/acs.jmedchem.7b00193.
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. 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. United States. https://doi.org/10.1021/acs.jmedchem.7b00193
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, and Wang, Shaomeng. Tue . "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". United States. https://doi.org/10.1021/acs.jmedchem.7b00193. https://www.osti.gov/servlets/purl/1373777.
@article{osti_1373777,
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},
author = {Zhao, Yujun and Bai, Longchuan and Liu, Liu and McEachern, Donna and Stuckey, Jeanne A. and Meagher, Jennifer L. and Yang, Chao-Yie and Ran, Xu and Zhou, Bing and Hu, Yang and Li, Xiaoqin and Wen, Bo and Zhao, Ting and Li, Siwei and Sun, Duxin and Wang, Shaomeng},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.7b00193},
journal = {Journal of Medicinal Chemistry},
number = 9,
volume = 60,
place = {United States},
year = {2017},
month = {5}
}

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