Inhibition of bromodomain-mediated protein–protein interactions as a novel therapeutic strategy

Furdas, Silviya D.; Carlino, Luca; Sippl, Wolfgang; Jung, Manfred

doi:10.1039/c1md00201e

Cited by 23 publications

(23 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The BET family proteins, especially BRD4, have recently been shown to play an important role in the pathways that cause multiple types of cancer, including acute myeloid leukemia (Zuber et al, 2011), mixed lineage leukemia (Dawson et al, 2011), multiple myeloma (Mertz et al, 2011), and an aggressive form of squamous carcinoma called NUT (nuclear protein in testis) midline carcinoma (Filippakopoulos et al, 2010; French et al, 2008; French et al, 2001; French et al, 2003; Reynoird et al, 2010). These clinically relevant studies have validated the BET bromodomains as attractive epigenetic cancer therapy targets, and also displayed the need for potent and selective bromodomain inhibitors (Belkina and Denis, 2012; Furdas et al, 2012; Muller et al, 2011). …”

Section: Diazepines As New Bromodomain Inhibitorsmentioning

confidence: 98%

Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors

Smith

Sánchez

Zhou

2014

Chemistry & Biology

View full text Add to dashboard Cite

Chemical compounds built on a diazepine scaffold have recently emerged as potent inhibitors of the acetyl-lysine binding activity of bromodomain-containing proteins, which is required for gene transcriptional activation in cancer and inflammation. Not only have these chemical compounds validated bromodomains as attractive epigenetic drug targets, but they have also brought to the forefront another application of the diazepine, which had already been regarded as a versatile chemical scaffold in rational drug design. This article reviews the success of diazepine compounds as therapeutic agents and examines the unique chemical and geometric features of this privileged scaffold that make it an excellent template for developing potent and selective molecules that control bromodomain-related gene expression in human diseases.

show abstract

Section: Diazepines As New Bromodomain Inhibitorsmentioning

confidence: 98%

Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors

Smith

Sánchez

Zhou

2014

Chemistry & Biology

View full text Add to dashboard Cite

show abstract

“…), are the only interaction modules that specifically recognize acetylated lysine residues of histones during transcriptional activation. [14][15][16][17][18] Many of BRDs are regulators of gene transcription such as histone acetyltransferases, components of chromatin remodeling complexes, and methyltransferases. 16,19 Human proteome analysis has revealed that there are eight distinct BRD families, representing 61 different BRDs from 46 separate proteins, although others may still be undiscovered.…”

Section: Introductionmentioning

confidence: 99%

Binding Kinetics versus Affinities in BRD4 Inhibition

Zhou

Wang

Liu

et al. 2015

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Bromodomains (BRDs) are protein modules that selectively recognize histones as a "reader" by binding to an acetylated lysine substrate. The human BRD4 has emerged as a promising drug target for a number of disease pathways, and several potent BRD inhibitors have been discovered experimentally recently. However, the detailed inhibition mechanism especially for the inhibitor binding kinetics is not clear. Herein, by employing classical molecular dynamics (MD) and state-of-the-art density functional QM/MM MD simulations, the dynamic characteristics of ZA-loop in BRD4 are revealed. And then the correlation between binding pocket size and ZA-loop motion is elucidated. Moreover, our simulations found that the compound (-)-JQ1 could be accommodated reasonably in thermodynamics whereas it is infeasible in binding kinetics against BRD4. Its racemate (+)-JQ1 proved to be both thermodynamically reasonable and kinetically achievable against BRD4, which could explain the previous experimental results that (+)-JQ1 shows a high inhibitory effect toward BRD4 (IC50 is 77 nM) while (-)-JQ1 is inactive (>10 μM). Furthermore, the L92/L94/Y97 in the ZA-loop and Asn140 in the BC-loop are identified to be critical residues in (+)-JQ1 binding/releasing kinetics. All these findings shed light on further selective inhibitor design toward BRD family, by exploiting the non-negligible ligand binding kinetics features and flexible ZA-loop motions of BRD, instead of only the static ligand-protein binding affinity.

show abstract

“…A number of small-molecule inhibitors of BET family members have now been published. 19 A key feature of these inhibitors is a KAc mimetic that anchors the molecule into the BRD binding site via hydrogen bonds and hydrophobic interactions, which is critical for potent binding. A limited number of chemotypes that possess these features had been published when this work started and has been increasing (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening

et al. 2013

View full text Add to dashboard Cite

Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.

show abstract

Inhibition of bromodomain-mediated protein–protein interactions as a novel therapeutic strategy

Abstract: Small molecule inhibitors of acetyl lysine–bromodomain interactions emerge as novel epigenetic tools with potential for therapeutic approaches.

Cited by 23 publications

References 83 publications

Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors

Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors

Binding Kinetics versus Affinities in BRD4 Inhibition

Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening

Contact Info

Product

Resources

About