Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities. Issue 12 (17th December 2015)

• Record Type: Journal Article
• Authors: Chekler, Eugene L. Piatnitski; Pellegrino, Jessica A.; Lanz, Thomas A.; Denny, R. Aldrin; Flick, Andrew C.; Coe, Jotham; Langille, Jonathan; Basak, Arindrajit; Liu, Shenping; Stock, Ingrid A.; Sahasrabudhe, Parag; Bonin, Paul D.; Lee, Kevin; Pletcher, Mathew T.; Jones, Lyn H.
• Is Part Of: Chemistry & biology. Volume 22:Issue 12(2015)
• Page Start: 1588
• Page End: 1596
• Publication Date: 2015-12-17
• Subjects: Biochemistry -- Periodicals; 540
• DOI: 10.1016/j.chembiol.2015.10.013
• Languages: English
• ISSNs: 1074-5521

Abstract

Summary: 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. Graphical Abstract: Highlights: PF-CBP1 is a highly selective inhibitor of the CREB binding protein bromodomain PF-CBP1 modulates key inflammatory genes in primary macrophages PF-CBP1 downregulates RGS4 in neurons, a target linked to Parkinson's disease Abstract : Chekler et al. designed, synthesized, and transcriptionally profiled a selective inhibitor of the bromodomain of CREB binding protein. The inhibitor, called PF-CBP1, modulated key inflammatory genes in macrophages and downregulated RGS4 (a gene linked to Parkinson's disease) in neurons.