Bromodomains and Their Pharmacological Inhibitors

Abstract

Over 60 bromodomains belonging to proteins with very different functions have been identified in humans. Several of them interact with acetylated lysine residues, leading to the recruitment and stabilization of protein complexes. The bromodomain and extra-terminal domain (BET) proteins contain tandem bromodomains which bind to acetylated histones and are thereby implicated in a number of DNA-centered processes, including the regulation of gene expression. The recent identification of inhibitors of BET and non-BET bromodomains is one of the few examples in which effective blockade of a protein-protein interaction can be achieved with a small molecule. This has led to major strides in the understanding of the function of bromodomain-containing proteins and their involvement in diseases such as cancer and inflammation. Indeed, BET bromodomain inhibitors are now being clinically evaluated for the treatment of hematological tumors and have also been tested in clinical trials for the relatively rare BRD-NUT midline carcinoma. This review gives an overview of the newest developments in the field, with a focus on the biology of selected bromodomain proteins on the one hand, and on reported pharmacological inhibitors on the other, including recent examples from the patent literature.

Epigenetics in rheumatoid arthritis

“…BET proteins are readers of the e-N-acetylation of lysine residues (Kac) on histone tails, a modification that is associated with an open chromatin architecture and transcriptional activation [36]. First clinical trials using the BET inhibitors I-BET762 for the treatment of nuclear protein in testis (NUT) midline carcinomas, OTX015 for the treatment of hematological malignancies and CPI-0610 for the treatment of lymphomas have started recently (reviewed in [37]), underscoring the potential of this class of inhibitors. However, BET inhibition as a point of therapeutic intervention also became of interest in autoimmune conditions because of the strong antiinflammatory properties of BET inhibitors [38,39].…”

“…Besides targeting bromodomain proteins [37], readers of other epigenetic marks including selected members of methyl-lysine binding site readers were predicted to have good drugability and first inhibitors are in development [43].…”

Cell-Based Protein Stabilization Assays for the Detection of Interactions between Small-Molecule Inhibitors and BRD4

“…The compound set contained small molecules with BRD4 binding activities ranging from double-digit nM to µM and included six reference compounds 10 (JQ1, I-BET762, I-BET151, CPI203, PFI-1, and the PFI-1 analogue Cpd 18; structures shown in Suppl. Fig.…”

“…The implication of BET proteins and mainly of BRD4 in cancer and in inflammatory processes has led to intensive efforts toward the identification of small-molecule inhibitors. 10,11 The triazolo-diazepines JQ1 and I-BET762 were among the first small molecules described to potently and selectively inhibit BET binding to acetylated histones, leading to strong antitumor activity in preclinical models. Very recently, a BET inhibitor has shown first signs of efficacy in the clinic, and several new inhibitors with different chemical scaffolds are currently being clinically characterized.…”

MYC and Chromatin

“…These compounds have been extensively reviewed elsewhere [167][168][169], so we will just touch on the highlights here. Collectively, bromodomain-containing proteins are noted for their ability to bind acetylated lysine residues, with BET subfamily members using dual bromodomains to recognize a suite of acetylated proteins, including histones H3 and H4 [170].…”