title: Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain.
abstract: Bromodomains are epigenetic reader domains that have recently become popular targets. In contrast to BET bromodomains, which have proven druggable, bromodomains from other regions of the phylogenetic tree have shallower pockets. We describe successful targeting of the challenging BAZ2B bromodomain using biophysical fragment screening and structure-based optimization of high ligand-efficiency fragments into a novel series of low-micromolar inhibitors. Our results provide attractive leads for development of BAZ2B chemical probes and indicate the whole family may be tractable.
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors.forename: Fleur M
authors.initials: FM
authors.lastname: Ferguson
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.forename: Martin
authors.initials: M
authors.lastname: Philpott
authors.forename: Joao R C
authors.initials: JR
authors.lastname: Muniz
authors.forename: Ildiko
authors.initials: I
authors.lastname: Felletar
authors.forename: Frank
authors.initials: F
authors.lastname: von Delft
authors.forename: Tom
authors.initials: T
authors.lastname: Heightman
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011506:Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D035165:Transcription Factors, General; D016335:Zinc Fingers / Q000187:drug effects*; D000092468:Bromodomain Containing Proteins
chemical_list: D008024:Ligands; D011506:Proteins; D035165:Transcription Factors, General; C000609272:BAZ2B protein, human; D000092468:Bromodomain Containing Proteins