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A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced‐Fit Pocket Stabilized by a Cation–π Interaction
Author(s) -
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.
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201402750
Subject(s) - bromodomain , chemistry , hydrogen bond , stereochemistry , series (stratigraphy) , combinatorial chemistry , molecule , biochemistry , histone , organic chemistry , dna , biology , paleontology
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.