title: Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.
abstract: Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Eugene L Piatnitski
authors.initials: EL
authors.lastname: Chekler
authors.affiliation: The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Pellegrino
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lanz
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: R Aldrin
authors.initials: RA
authors.lastname: Denny
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Flick
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Jotham
authors.initials: J
authors.lastname: Coe
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langille
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Arindrajit
authors.initials: A
authors.lastname: Basak
authors.affiliation: Structural Biology and Biophysics, Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Stock
authors.affiliation: Structural Biology and Biophysics, Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Parag
authors.initials: P
authors.lastname: Sahasrabudhe
authors.affiliation: Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bonin
authors.affiliation: Rare Disease Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Rare Disease Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Mathew T
authors.initials: MT
authors.lastname: Pletcher
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, 610 Main Street, Cambridge, MA 02139, USA. Electronic address: lyn.jones@pfizer.com.
authors.forename: Lyn H
authors.initials: LH
authors.lastname: Jones
mesh_terms: D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D020710:RGS Proteins; D054852:Small Molecule Libraries; C098799:RGS4 protein; D050882:CREB-Binding Protein; C494363:CREBBP protein, human