title: Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain.
abstract: Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).
authors.affiliation: Medicine Design, Pfizer , 610 Main Street, Cambridge Massachusetts 02139, United States.
authors.forename: R Aldrin
authors.identifier: 0000-0001-7441-7077
authors.initials: RA
authors.lastname: Denny
authors.affiliation: Medicine Design, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Flick
authors.affiliation: Medicine Design, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
authors.forename: Jotham
authors.initials: J
authors.lastname: Coe
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langille
authors.affiliation: Medicine Design, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
authors.forename: Arindrajit
authors.initials: A
authors.lastname: Basak
authors.affiliation: Structural Biology and Biophysics, Medicine Design, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stock
authors.affiliation: Structural Biology and Biophysics, Medicine Design, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
authors.forename: Parag
authors.initials: P
authors.lastname: Sahasrabudhe
authors.affiliation: Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Bonin
authors.affiliation: Evotec (UK) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.|Structural Genomics Consortium, Target Discovery Institute, ARUK Oxford Drug Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Duncan A
authors.initials: DA
authors.lastname: Hay
authors.affiliation: Structural Genomics Consortium, Target Discovery Institute, ARUK Oxford Drug Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, U.K.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: Rare Disease Research Unit, Pfizer , 610 Main Street, Cambridge Massachusetts 02139, United States.
authors.forename: Mathew
authors.initials: M
authors.lastname: Pletcher
authors.affiliation: Medicine Design, Pfizer , 610 Main Street, Cambridge Massachusetts 02139, United States.
authors.forename: Lyn H
authors.identifier: 0000-0002-8388-5865
authors.initials: LH
authors.lastname: Jones
authors.affiliation: Medicine Design, Pfizer , 610 Main Street, Cambridge Massachusetts 02139, United States.
authors.forename: Eugene L Piatnitski
authors.initials: ELP
authors.lastname: Chekler
mesh_terms: D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009025:Morpholines; C037574:morpholine; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human