title: Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening.
abstract: The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains. High-resolution crystal structures of the complexes of key fragments binding to BRD4(1), CREBBP, and PCAF were determined to provide binding mode data to aid the development of potent and selective inhibitors of PCAF, CREBBP, and BRD4.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, United Kingdom.
authors.forename: Iva
authors.initials: I
authors.lastname: Navratilova
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, United Kingdom.
authors.forename: Tonia
authors.initials: T
authors.lastname: Aristotelous
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom; Ludwig Institute for Cancer Research, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filappakopoulos
authors.affiliation: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, United Kingdom.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hopkins
keywords: BRD4; Bromodomains; CREBBP; PCAF; fragment screening; surface plasmon resonance