The posttranslational modification of chromatin through acetylation at selected 
histone lysine residues is governed by histone acetyltransferases (HATs) and 
histone deacetylases (HDACs). The significance of this subset of the epigenetic 
code is interrogated and interpreted by an acetyllysine-specific protein-protein 
interaction with bromodomain reader modules. Selective inhibition of the bromo 
and extra C-terminal domain (BET) family of bromodomains with a small molecule 
is feasible, and this may represent an opportunity for disease intervention 
through the recently disclosed antiproliferative and anti-inflammatory 
properties of such inhibitors. Herein, we describe the discovery and 
structure-activity relationship (SAR) of a novel, small-molecule chemical probe 
for BET family inhibition that was identified through the application of 
structure-based fragment assessment and optimization techniques. This has 
yielded a potent, selective compound with cell-based activity (PFI-1) that may 
further add to the understanding of BET family function within the bromodomains.