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Title: Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor

Abstract

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 NH-pyrazole group into the 9H-pyrimido[4,5-b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with Ki 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 in 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. Furthermore, these data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.

Authors:
 [1]; ORCiD logo [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [3];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2]; ORCiD logo [2]
+ Show Author Affiliations
  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:
1471643
Grant/Contract Number:  
AC02-06CH11357; P50 CA186786; P30CA046592; 085P1000817
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 14; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; rodent models; inhibitors; inhibition; cancer; screening assays

Citation Formats

Zhao, Yujun, Zhou, Bing, Bai, Longchuan, Liu, Liu, Yang, Chao-Yie, Meagher, Jennifer L., Stuckey, Jeanne A., McEachern, Donna, Przybranowski, Sally, Wang, Mi, Ran, Xu, Aguilar, Angelo, Hu, Yang, Kampf, Jeff W., Li, Xiaoqin, Zhao, Ting, Li, Siwei, Wen, Bo, Sun, Duxin, and Wang, Shaomeng. Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.8b00483.
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Zhao, Yujun, Zhou, Bing, Bai, Longchuan, Liu, Liu, Yang, Chao-Yie, Meagher, Jennifer L., Stuckey, Jeanne A., McEachern, Donna, Przybranowski, Sally, Wang, Mi, Ran, Xu, Aguilar, Angelo, Hu, Yang, Kampf, Jeff W., Li, Xiaoqin, Zhao, Ting, Li, Siwei, Wen, Bo, Sun, Duxin, & Wang, Shaomeng. Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor. United States. https://doi.org/10.1021/acs.jmedchem.8b00483
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Zhao, Yujun, Zhou, Bing, Bai, Longchuan, Liu, Liu, Yang, Chao-Yie, Meagher, Jennifer L., Stuckey, Jeanne A., McEachern, Donna, Przybranowski, Sally, Wang, Mi, Ran, Xu, Aguilar, Angelo, Hu, Yang, Kampf, Jeff W., Li, Xiaoqin, Zhao, Ting, Li, Siwei, Wen, Bo, Sun, Duxin, and Wang, Shaomeng. Sun . "Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor". United States. https://doi.org/10.1021/acs.jmedchem.8b00483. https://www.osti.gov/servlets/purl/1471643.
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@article{osti_1471643,
title = {Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor},
author = {Zhao, Yujun and Zhou, Bing and Bai, Longchuan and Liu, Liu and Yang, Chao-Yie and Meagher, Jennifer L. and Stuckey, Jeanne A. and McEachern, Donna and Przybranowski, Sally and Wang, Mi and Ran, Xu and Aguilar, Angelo and Hu, Yang and Kampf, Jeff W. and Li, Xiaoqin and Zhao, Ting and Li, Siwei and Wen, Bo and Sun, Duxin and Wang, Shaomeng},
abstractNote = {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 NH-pyrazole group into the 9H-pyrimido[4,5-b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with Ki 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 in 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. Furthermore, these data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.},
doi = {10.1021/acs.jmedchem.8b00483},
journal = {Journal of Medicinal Chemistry},
number = 14,
volume = 61,
place = {United States},
year = {Sun Jun 17 00:00:00 EDT 2018},
month = {Sun Jun 17 00:00:00 EDT 2018}
}
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https://doi.org/10.1021/acs.jmedchem.8b00483
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    Works referencing / citing this record:

    BET bromodomain inhibitors: fragment-based in silico design using multi-target QSAR models
    journal, November 2018

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