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

Authors:
; ; ; ; ; ; ORCiD logo; ; ORCiD logo; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
UNIVERSITYNIH
OSTI Identifier:
1373777
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 9
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES

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. doi: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. doi: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. Fri . "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. doi:10.1021/acs.jmedchem.7b00193.
@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. 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 = {Fri Mar 24 00:00:00 EDT 2017},
month = {Fri Mar 24 00:00:00 EDT 2017}
}