2. Academic Validation
  3. Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit

  • J Med Chem. 2016 May 26;59(10):4800-11. doi: 10.1021/acs.jmedchem.6b00012.
Brian S Gerstenberger 1,  John D Trzupek 1,  Cynthia Tallant 2 3,  Oleg Fedorov 2 3,  Panagis Filippakopoulos 2 4,  Paul E Brennan 2 3,  Vita Fedele 2 3,  Sarah Martin 2 3,  Sarah Picaud 2 3,  Catherine Rogers 2 3,  Mihir Parikh 5,  Alexandria Taylor 5,  Brian Samas 6,  Alison O'Mahony 7,  Ellen Berg 7,  Gabriel Pallares 8,  Adam D Torrey 8,  Daniel K Treiber 8,  Ivan J Samardjiev 9,  Brian T Nasipak 10,  Teresita Padilla-Benavides 10,  Qiong Wu 10,  Anthony N Imbalzano 10,  Jeffrey A Nickerson 10,  Mark E Bunnage 1,  Susanne Müller 2 3,  Stefan Knapp 2 3 11,  Dafydd R Owen 1
Affiliations

Affiliations

  • 1 Pfizer Worldwide Medicinal Chemistry , 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 2 Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, United Kingdom.
  • 3 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
  • 4 Ludwig Institute for Cancer Research, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
  • 5 Pfizer Pharmaceutical Sciences , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 6 Pfizer Worldwide Medicinal Chemistry , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 7 Bioseek Inc., Division of DiscoveRx , 310 Utah Avenue, South San Francisco, California 94080, United States.
  • 8 KinomeScan, Division of DiscoveRx , 11180 Roselle Street, Suite D, San Diego, California 92121, United States.
  • 9 Eurofins Lancaster PPS , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 10 Department of Cell and Developmental Biology, University of Massachusetts Medical School , Worcester, Massachusetts 01655, United States.
  • 11 Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences (BMLS), Johann Wolfgang Goethe University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
PMID: 27115555 DOI: 10.1021/acs.jmedchem.6b00012
Abstract

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.

Figures
Products