Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities

Eugene L Piatnitski Chekler; Jessica A Pellegrino; Thomas A Lanz; R Aldrin Denny; Andrew C Flick; Jotham Coe; Jonathan Langille; Arindrajit Basak; Shenping Liu; Ingrid A Stock; Parag Sahasrabudhe; Paul D Bonin; Kevin Lee; Mathew T Pletcher; Lyn H Jones

doi:10.1016/j.chembiol.2015.10.013

Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities

Chem Biol. 2015 Dec 17;22(12):1588-96. doi: 10.1016/j.chembiol.2015.10.013. Epub 2015 Dec 3.

Authors

Affiliations

¹ Worldwide Medicinal Chemistry, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
² The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
³ Neuroscience and Pain Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
⁴ Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
⁵ Structural Biology and Biophysics, Worldwide Medicinal Chemistry, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
⁶ Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
⁷ Rare Disease Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
⁸ Worldwide Medicinal Chemistry, Pfizer, 610 Main Street, Cambridge, MA 02139, USA. Electronic address: [email protected].

PMID: 26670081
DOI: 10.1016/j.chembiol.2015.10.013

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.

MeSH terms

CREB-Binding Protein / antagonists & inhibitors*
CREB-Binding Protein / genetics
Drug Design*
Fluorescence Resonance Energy Transfer
Gene Expression Regulation / drug effects
Humans
Protein Structure, Tertiary
RGS Proteins / genetics
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology
Transcriptome

Substances

RGS Proteins
Small Molecule Libraries
RGS4 protein
CREB-Binding Protein
CREBBP protein, human

Associated data

PDB/5CFW
PDB/5CGP