A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation-π Interaction

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...

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Bibliographic Details
Published in:Angewandte Chemie 2014-06, Vol.126 (24), p.6240-6244
Main Authors: Rooney, Timothy P. C., Filippakopoulos, Panagis, Fedorov, Oleg, Picaud, Sarah, Cortopassi, Wilian A., Hay, Duncan A., Martin, Sarah, Tumber, Anthony, Rogers, Catherine M., Philpott, Martin, Wang, Minghua, Thompson, Amber L., Heightman, Tom D., Pryde, David C., Cook, Andrew, Paton, Robert S., Müller, Susanne, Knapp, Stefan, Brennan, Paul E., Conway, Stuart J.
Format: Article
Language:English
Subjects:
Affinity
Binding
Bromodomänen
Cations
Chains
CREBBP
Enzyminhibitoren
Epigenetik
Hydrogen bonds
Inhibitors
Ligandendesign
Ligands
Lysine
Pocket
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Summary: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. Passende Liganden: Dihydrochinoxalinonfragmente dienten als Acetyllysin‐Mimetika in der Entwicklung von Liganden für die CREBBP‐Bromodomäne, deren Seitenkette in eine Tasche mit induzierter Passform bindet und eine Kation‐π‐Wechselwirkung mit R1173 von CREBBP bildet. Die wirksamste Verbindung inhibiert die Bindung von CREBBP an Chromatin in U2OS‐Zellen.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201402750