I. Felletar

TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.

TL;DR: Bromodomains are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks, and a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4 is uncovered.

TL;DR: The discovery and characterization of RVX-208 as a domain-selective inhibitor of BETs and a potential mechanism of action of a clinical compound that was identified based on phenotypic screens are reported and demonstrated.

TL;DR: High-throughput assays that quantify the binding of bromodomains to acetylated histone peptides are reported, and it is demonstrated that these assays can be used to detect small molecule binding from the very weak to the nanomolar range.

TL;DR: This work describes successful targeting of the challenging BAZ2B bromodomain using biophysical fragment screening and structure-based optimization of high ligand-efficiency fragments into a novel series of low-micromolar inhibitors.