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Title: Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors

Abstract

Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1405004
Resource Type:
Journal Article
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 3; Journal Issue: 6; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Cho, Young Shin, Angove, Hayley, Brain, Christopher, Chen, Christine Hiu-Tung, Cheng, Hong, Cheng, Robert, Chopra, Rajiv, Chung, Kristy, Congreve, Miles, Dagostin, Claudio, Davis, Deborah J., Feltell, Ruth, Giraldes, John, Hiscock, Steven D., Kim, Sunkyu, Kovats, Steven, Lagu, Bharat, Lewry, Kim, Loo, Alice, Lu, Yipin, Luzzio, Michael, Maniara, Wiesia, McMenamin, Rachel, Mortenson, Paul N., Benning, Rajdeep, O'Reilly, Marc, Rees, David C., Shen, Junqing, Smith, Troy, Wang, Yaping, Williams, Glyn, Woolford, Alison J. -A., Wrona, Wojciech, Xu, Mei, Yang, Fan, and Howard, Steven. Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors. United States: N. p., 2012. Web. doi:10.1021/ml200241a.
Cho, Young Shin, Angove, Hayley, Brain, Christopher, Chen, Christine Hiu-Tung, Cheng, Hong, Cheng, Robert, Chopra, Rajiv, Chung, Kristy, Congreve, Miles, Dagostin, Claudio, Davis, Deborah J., Feltell, Ruth, Giraldes, John, Hiscock, Steven D., Kim, Sunkyu, Kovats, Steven, Lagu, Bharat, Lewry, Kim, Loo, Alice, Lu, Yipin, Luzzio, Michael, Maniara, Wiesia, McMenamin, Rachel, Mortenson, Paul N., Benning, Rajdeep, O'Reilly, Marc, Rees, David C., Shen, Junqing, Smith, Troy, Wang, Yaping, Williams, Glyn, Woolford, Alison J. -A., Wrona, Wojciech, Xu, Mei, Yang, Fan, & Howard, Steven. Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors. United States. doi:10.1021/ml200241a.
Cho, Young Shin, Angove, Hayley, Brain, Christopher, Chen, Christine Hiu-Tung, Cheng, Hong, Cheng, Robert, Chopra, Rajiv, Chung, Kristy, Congreve, Miles, Dagostin, Claudio, Davis, Deborah J., Feltell, Ruth, Giraldes, John, Hiscock, Steven D., Kim, Sunkyu, Kovats, Steven, Lagu, Bharat, Lewry, Kim, Loo, Alice, Lu, Yipin, Luzzio, Michael, Maniara, Wiesia, McMenamin, Rachel, Mortenson, Paul N., Benning, Rajdeep, O'Reilly, Marc, Rees, David C., Shen, Junqing, Smith, Troy, Wang, Yaping, Williams, Glyn, Woolford, Alison J. -A., Wrona, Wojciech, Xu, Mei, Yang, Fan, and Howard, Steven. Thu . "Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors". United States. doi:10.1021/ml200241a.
@article{osti_1405004,
title = {Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors},
author = {Cho, Young Shin and Angove, Hayley and Brain, Christopher and Chen, Christine Hiu-Tung and Cheng, Hong and Cheng, Robert and Chopra, Rajiv and Chung, Kristy and Congreve, Miles and Dagostin, Claudio and Davis, Deborah J. and Feltell, Ruth and Giraldes, John and Hiscock, Steven D. and Kim, Sunkyu and Kovats, Steven and Lagu, Bharat and Lewry, Kim and Loo, Alice and Lu, Yipin and Luzzio, Michael and Maniara, Wiesia and McMenamin, Rachel and Mortenson, Paul N. and Benning, Rajdeep and O'Reilly, Marc and Rees, David C. and Shen, Junqing and Smith, Troy and Wang, Yaping and Williams, Glyn and Woolford, Alison J. -A. and Wrona, Wojciech and Xu, Mei and Yang, Fan and Howard, Steven},
abstractNote = {Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.},
doi = {10.1021/ml200241a},
journal = {ACS Medicinal Chemistry Letters},
issn = {1948-5875},
number = 6,
volume = 3,
place = {United States},
year = {2012},
month = {6}
}