Journal article
A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-π interaction
- Abstract:
- The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein‐bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced‐fit pocket forming a cation–π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 2.0MB, Terms of use)
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- Publisher copy:
- 10.1002/anie.201402750
Authors
- Publisher:
- Wiley‐VCH Verlag
- Journal:
- Angewandte Chemie (International ed. in English) More from this journal
- Volume:
- 53
- Issue:
- 24
- Pages:
- 6126-6130
- Publication date:
- 2014-05-12
- DOI:
- EISSN:
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1521-3773
- ISSN:
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1433-7851
- Language:
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English
- Keywords:
- UUID:
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uuid:6fa6267a-c739-4acc-be90-a1b602e746e9
- Local pid:
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pubs:464925
- Source identifiers:
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464925
- Deposit date:
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2014-05-20
Terms of use
- Copyright holder:
- Rooney et al
- Copyright date:
- 2014
- Notes:
- Copyright © 2014 The Authors. Published by Wiley‐VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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