Reports

Brdt play key roles in transcriptional regulation by controlling networks of genes involved in cellular proliferation and cell cycle regulation as part of multiprotein complexes. Misregulation of BET proteins activity has been linked to disease states, notably in NUT-midline carcinoma and other cancers (1). Key to the activity of BET proteins are paired, highly homologous bromodomains present in their amino-terminal regions (Fig. 1A) that direct recruitment to nucleosomes by specifically binding to acetylated lysines within histone tails. Elucidation of the complex bio-logical processes controlled by BET proteins would benefit greatly from chemical probes that allow perturbation of individual bromodomains with high selectivity. Potent cell-active small molecules based on a triazolodiazepine scaf-fold including I-BET (2), JQ1 (3) and GW841819X (4) (Fig. 1B) were recently discovered that bind to the acetyl-lysine (KAc) binding pocket of BET bromodomains (Kds 50-370 nM for I-BET, Fig. 1C, Table S