title: Small molecule inhibitors of bromodomain-acetyl-lysine interactions.
abstract: Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain-acetyl-lysine protein-protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
authors.forename: Michael
authors.initials: M
authors.lastname: Brand
authors.forename: Angelina R
authors.initials: AR
authors.lastname: Measures
authors.forename: Angelina M
authors.initials: AM
authors.lastname: Measures
authors.forename: Brian G
authors.initials: BG
authors.lastname: Wilson
authors.forename: Wilian A
authors.initials: WA
authors.lastname: Cortopassi
authors.forename: Rikki
authors.initials: R
authors.lastname: Alexander
authors.forename: Matthias
authors.initials: M
authors.lastname: Höss
authors.forename: David S
authors.initials: DS
authors.lastname: Hewings
authors.forename: Timothy P C
authors.initials: TP
authors.lastname: Rooney
authors.forename: Robert S
authors.initials: RS
authors.lastname: Paton
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Conway
mesh_terms: D000107:Acetylation; D000818:Animals; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000378:metabolism*; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006657:Histones; D008024:Ligands; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D008239:Lysine