Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 53, Issue 24, Pages 6126-6130Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201402750
Keywords
bromodomain; CREBBP; enzyme inhibitors; epigenetics; ligand discovery
Categories
Funding
- Pfizer Neusentis
- EPSRC
- SGC [1097737]
- AbbVie
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z, 095751/Z/11/Z]
- Science Without Borders (CAPES)
- Wellcome Trust [095751/Z/11/Z] Funding Source: Wellcome Trust
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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-pi interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.
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