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Targeting bromodomains: epigenetic readers of lysine acetylation

Key Points

  • Bromodomains are acetyl-lysine-specific protein interaction modules present in proteins that have key roles in the regulation of gene transcription.

  • Aberrant acetylation levels and dysfunction of bromodomain-containing proteins lead to deregulation of transcriptional programmes; this has been linked to the development of several diseases, including cancer, inflammation and viral infection.

  • The recent discovery of potent and highly specific inhibitors for bromodomains of the BET family (BRD2, BRD3, BRD4 and BRDT) has stimulated intensive research activity in different therapeutic areas, particularly in oncology, where BET inhibitors have now entered clinical testing.

  • Generally good druggability has also been predicted for non-BET bromodomains, which suggests that the bromodomain family may emerge as a major new target class for the development of new pharmaceuticals.

Abstract

Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programmes that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncology, where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addition, targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery.

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Figure 1: Histone modifications and their readout in the context of chromatin.
Figure 2: Bromodomain family: structure and acetyl-lysine peptide recognition.
Figure 3: Predicted druggability and binding of small molecules to bromodomains.
Figure 4: Binding orientations of inhibitors to bromodomain modules.
Figure 5: Major subclasses of acetyl-lysine mimetic inhibitors that potently inhibit bromodomains.
Figure 6: BET fusions with NUT and mechanism of transcriptional regulation by BRD4.

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Acknowledgements

We apologize to all authors whose important contributions could not be acknowledged owing to space limitations. The authors are grateful for support for their research received from the the Structural Genomics Consortium (SGC), a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Pfizer, Eli Lilly, Takeda, AbbVie, the Novartis Research Foundation, Bayer, the Ontario Ministry of Research and Innovation, and the Wellcome Trust (092809/Z/10/Z). The work of P.F. is supported by a Wellcome Trust Career-Development Fellowship (095751/Z/11/Z).

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FURTHER INFORMATION

Annotated Phylogenetic Trees — SGC website

Chemical Probes — SGC website

Epigenetics Probe Collection — SGC website

ESC Congress report (“ASSURE: Effect of an Oral Agent Inducing Apo A-I Synthesis on Progression of Coronary Atherosclerosis: Results of the ASSURE Study”) — European Society of Cardiology

GSK2801 overview — SGC website

ICBP112 overview — SGC website

JQ1/SGCBD01 overview — SGC website

PFI-1 overview — SGC website

Resverlogix — 3 September 2013 press release (“Further Analysis of the ASSURE Data Finds a Responder Group for RVX-208 with Statistically Significant Regression of Coronary Atherosclerosis”)

SGC-CBP30 overview — SGC website

DATABASES

ChEMBL Database

ChEpiMod Knowledgebase

ClinicalTrials.gov website

Dictionary of Natural Products

PhosphoSitePlus database

Protein Data Bank

ZINC Library

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Patented Bromodomain Inhibitor Series (PDF 260 kb)

Supplementary information S2 (table)

Bromodomain ligand complexes (PDF 476 kb)

Glossary

Nuclear factor-κB

(NF-κB). A protein complex that controls gene transcription. It has a key role regulation of the immune response that is initiated owing to infection. Its deregulation has been linked to the pathogenesis of cancer, inflammation and viral infection.

Chemotypes

Chemically distinct entities with differences in the composition of their secondary metabolites.

Chemical scaffolds

Molecular backbone of a molecule on which functional groups are altered during drug design.

Druggability scores

Numerical quantities that are calculated from experimental structural data and that assess the druggability of structures by taking into account the contributions from the volume, the level of enclosure and the degree of hydrophobicity of a pocket towards the binding of small molecules.

Histac

A technology that relies on conformational changes upon acetylation. This change alters the fluorescence resonance energy transfer (FRET) that is generated when a histone peptide is fused to the bromodomain-containing protein BRDT and further fused in tandem with the donor and acceptor protein.

Lipinski's rule-of-five guidelines

A rule of thumb formulated by Christopher Lipinski in 1997, based on the observation that most medications are relatively small and lipophilic molecules. These guidelines are used to evaluate drug-likeness or determine whether a chemical compound with a certain pharmacological or biological activity has properties that would make it likely to be an orally active drug in humans.

LC–MS/MS

An analytical chemistry technique that combines the physical separation capabilities of liquid chromatography (LC) with the mass analysis capabilities of tandem mass spectrometry (MS/MS), a process that involves multiple steps of mass spectrometry selection, with some form of fragmentation occurring in between the stages of selection.

Liver microsomes

A model system used in in vitro ADME (absorption, distribution, metabolism and excretion) studies. Liver microsomes contain a variety of drug-metabolizing enzymes, and so they are used to examine the potential for first-pass metabolism of orally administered drugs.

Ligand efficiency

A metric used to aid the selection of lead compounds with optimal combinations of physicochemical properties and pharmacological properties, relying on the measurement of the binding energy per atom of a ligand to its binding partner, such as a receptor or enzyme.

NUT midline carcinoma

(NMC). A highly aggressive and poorly differentiated squamous cell carcinoma that predominantly occurs in children and young adults. NMC mainly arises in the midline of the body, commonly in the head, neck or mediastinum, and is caused by translocation of the nuclear protein in testis (NUT) gene.

Positive transcription elongation factor B

(PTEFB). A complex that is made up of cyclin-dependent kinase 9 (CDK9) and its activator cyclin T, which phosphorylates RNA polymerase II. PTEFB is recruited to chromatin by the bromodomain-containing proteins BRD4 and BRDT.

Enhancers

Short DNA sequences that recruit transcription factors and co-activators that form the enhanceosome, which acts cooperatively to strongly stimulate the transcription of various sets of genes.

Super enhancer

Large enhancer regions that stimulate the transcription of growth-promoting and lineage-specific survival genes.

Oncogene addiction

The physiological dependence of tumour cells to certain growth-promoting genes (oncogenes). This dependence is responsible for maintaining a malignant phenotype.

Mediator complex

A large distal multiprotein complex that acts as a transcriptional co-activator. Its large surface area provides great potential for protein–protein interactions, even though its sequences do not contain many predicted functional domains.

Primary response genes

A set of genes that are induced in response to both cell-extrinsic and cell-intrinsic signals and do not require de novo protein synthesis for their expression. They have pivotal roles in many biological responses, including neuronal survival and plasticity, the cardiac stress response, as well as innate and adaptive immune responses.

CpG islands

Genomic DNA regions that contain a high frequency of sites consisting of cytosine and guanine residues connected by a phosphodiester bond (known as CpG sites). They are usually found at or near the transcription start site of genes.

RELA

A protein that is part of the nuclear factor-κB complex. Bromodomains found in bromodomain-containing protein 4 (BRD4) can bind to acetylated Lys330 of RELA.

T helper 17 cells

(TH17 cells). A subset of TH cells that have an essential role in the immune response controlling fungal and bacterial infections; aberrant activation of TH17 cells — which secrete interleukin-17 — is a hallmark of autoimmune diseases.

HIV latency

A stage of the HIV life cycle that follows acute infection, in which HIV resides in CD4+ T cells and replicates at very low levels. Current antiviral therapy cannot target latent HIV.

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Filippakopoulos, P., Knapp, S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 13, 337–356 (2014). https://doi.org/10.1038/nrd4286

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