title: Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain.
abstract: The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, U.K.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Steffen
authors.initials: S
authors.lastname: Lang
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, U.K.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: Leiden Institute of Chemistry, Leiden University , Einsteinweg 55, 2333 CC Leiden, Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Temperini
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, U.K.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: ZoBio , Einsteinweg 55, 2333 CC Leiden, Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Hollander
authors.affiliation: ZoBio , Einsteinweg 55, 2333 CC Leiden, Netherlands.
authors.forename: Ruta
authors.initials: R
authors.lastname: Nachane
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, U.K.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: ZoBio , Einsteinweg 55, 2333 CC Leiden, Netherlands.
authors.forename: Gregg
authors.initials: G
authors.lastname: Siegal
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, U.K.|Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University and Buchmann Institute for Molecular Life Sciences , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor