title: 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.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK) http://conway.chem.ox.ac.uk/
authors.forename: Timothy P C
authors.initials: TP
authors.lastname: Rooney
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: Wilian A
authors.initials: WA
authors.lastname: Cortopassi
authors.forename: Duncan A
authors.initials: DA
authors.lastname: Hay
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rogers
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.forename: Minghua
authors.initials: M
authors.lastname: Wang
authors.forename: Amber L
authors.initials: AL
authors.lastname: Thompson
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde
authors.forename: Andrew
authors.initials: A
authors.lastname: Cook
authors.forename: Robert S
authors.initials: RS
authors.lastname: Paton
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Conway
mesh_terms: D050882:CREB-Binding Protein / Q000235:genetics*; D002412:Cations / Q000737:chemistry*; D057890:Epigenomics / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D002412:Cations; D008024:Ligands; D050882:CREB-Binding Protein; C494363:CREBBP protein, human
keywords: CREBBP; bromodomain; enzyme inhibitors; epigenetics; ligand discovery