Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain

J Med Chem. 2016 Feb 25;59(4):1648-53. doi: 10.1021/acs.jmedchem.5b01719. Epub 2016 Jan 13.


The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary / drug effects
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • p300-CBP Transcription Factors / antagonists & inhibitors*
  • p300-CBP Transcription Factors / chemistry
  • p300-CBP Transcription Factors / metabolism*


  • Ligands
  • Small Molecule Libraries
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor