Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions

Abstract

Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain-acetyl-lysine protein-protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design.

BRD4 Structure–Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

“…The potent binding affinity of 39j places it among the most active BRD4 inhibitors known 14 and its increased affinity over BI-2536 might be explained by hydrophobic interactions with the WPF shelf. Notably, compound 39j bound PLK1 25-fold weaker than BI-2536, such that affinities for BRD4 and PLK1 had become effectively equipotent.…”

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

“…1a) 7,8 . Recent studies have reported the complete or partial displacement of this four-water network.…”

Structure of the Brd4 ET domain bound to a C-terminal motif from γ-retroviral integrases reveals a conserved mechanism of interaction

“…1A). The dual bromodomains recognize and bind acetylated lysines on histone H3 and H4 tails on chromatin (9)(10)(11), thereby tethering the protein and any associated factors to those histone posttranslational modifications (PTMs). Whereas recognition of select histone marks is achieved through the bromodomains, the overall high-affinity binding to chromatin is the result of cooperative binding to both its cognate PTMs and nonspecific binding to DNA wrapped around mononucleosomes through interaction with the conserved motifs A and B (12,13).…”

“…The interaction with NSD3 underlies an aggressive midline carcinoma resulting from a chromosomal translocation that fuses Brd4 with nuclear protein in testes (16). Owing to their role in cell cycle regulation and epigenetic sensing, as well as associations with a range of disease states, the therapeutic potential of targeting BET proteins with small molecule inhibitors is an area of intense interest, most of which is centered on preventing chromatin binding by the bromodomains (10,11).…”