2. Academic Validation
  3. Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities

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.
Eugene L Piatnitski Chekler 1,  Jessica A Pellegrino 2,  Thomas A Lanz 3,  R Aldrin Denny 1,  Andrew C Flick 4,  Jotham Coe 4,  Jonathan Langille 4,  Arindrajit Basak 4,  Shenping Liu 5,  Ingrid A Stock 6,  Parag Sahasrabudhe 5,  Paul D Bonin 6,  Kevin Lee 7,  Mathew T Pletcher 7,  Lyn H Jones 8
Affiliations

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.

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