Drug Discovery Targeting Bromodomain-Containing Protein 4

Liu, Zhiqing; Wang, Pingyuan; Chen, Haiying; Wold, Eric A.; Tian, Bing; Brasier, Allan R.; Zhou, Jia

doi:10.1021/acs.jmedchem.6b01761

Cited by 256 publications

(332 citation statements)

References 177 publications

(388 reference statements)

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“…Despite significant effort invested in the development of small molecule BRD4 inhibitors, none have been yet reported that are highly selective for BRD4 over other members of the BET family (Liu et al, 2017). To this end, by utilizing a structure-based drug design for the KAc binding pocket, ZL-0420 and ZL-0454, containing a dihydroquinolin-2(1 H )-one or N -cyclopentyl-benzenesulfonamide binding tail, were synthesized.…”

Section: Resultsmentioning

confidence: 99%

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Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation

Tian¹,

Liu

Yang³

et al. 2018

Cell Reports

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SUMMARY The mechanisms how the mammalian airway detects invading viral pathogens to trigger protective innate neutrophilic inflammation are incompletely understood. We observe that innate activation of the NFκB/RelA transcription factor indirectly activates atypical BRD4 histone acetyltransferase (HAT) activity, RNA Polymerase II (Pol II) phosphorylation, and secretion of neutrophilic chemokines. To study this pathway in vivo, we develop a conditional knockout of RelA in the distal airway epithelial cell; these animals have reduced mucosal BRD4/Pol II activation and neutrophilic inflammation to viral patterns. To further understand the role of BRD4 in vivo, two potent, highly selective small-molecule BRD4 inhibitors were developed. These well-tolerated inhibitors disrupt BRD4 complex with Pol II and histones, completely blocking inducible epithelial chemokine production and neutrophilia. We conclude RelA-BRD4 signaling in distal tracheobronchiolar epithelial cells mediates acute inflammation in response to luminal viral patterns. These potent BRD4 antagonists are versatile pharmacological tools for investigating BRD4 functions in vivo.

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Section: Resultsmentioning

confidence: 99%

“…Because of its diverse roles in inflammation, cancer and fibrosis, development of BRD4 inhibitors have been the subject of intense focus (Liu et al, 2017). In this study, we have applied structure-based drug design to advance the pharmacopeia of BRD4 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation

Tian¹,

Liu

Yang³

et al. 2018

Cell Reports

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“…Fusions of BRD3/4 with the protein Nuclear in Testis give rise to NUT midline carcinoma, an aggressive malignancy, and BRD4 has been shown to occupy super-enhancer regions that drive oncogenic transcription programs in a range of cancers (21)(22)(23)(24)(25). As a consequence, BRD4 in particular has become a major target for the design of cancer therapeutics that inhibit the acetyllysine-binding properties of its bromodomains (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators

Wai

Szyszka

Campbell

et al. 2018

Journal of Biological Chemistry

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Members of the bromodomain and extraterminal domain (BET) family of proteins (bromodomain-containing (BRD) 2, 3, 4 and T) are widely expressed and highly conserved regulators of gene expression in eukaryotes. These proteins have been intimately linked to human disease and more than a dozen clinical trials are currently underway to test BET-protein inhibitors as modulators of cancer therapies. However, although it is clear that these proteins use their bromodomains to bind both histones and transcription factors bearing acetylated lysine residues, the molecular mechanisms by which BET-family proteins regulate gene expression are not well defined. In particular, the functions of the other domains such as the ET domain have been less extensively studied. Here, we examine the properties of the ET domain of BRD3 as a protein-protein interaction module. Using a combination of pulldown and biophysical assays, we demonstrate that BRD3 binds to a range of chromatin-remodeling complexes, including the NuRD, BAF and INO80 complexes, via a short linear 'KIKL' motif in one of the complex subunits. NMRbased structural analysis revealed that, surprisingly, this mode of interaction is shared by the AF9 and ENL transcriptional coregulators that contain an acetyllysine-binding YEATS domain and regulate transcriptional elongation. This observation establishes a functional commonality between these two families of cancer-related transcriptional regulators. In summary, our data provide insight into the mechanisms by which BET-family proteins might link chromatin acetylation to transcriptional outcomes and uncover an unexpected functional similarity between BET and YEATS family proteins.

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“…The discovery of new BRD4 inhibitors may provide reference for drug design and make a contribution to the treatment of cancer or other diseases. Currently, more than a dozen of BRD4 inhibitors have progressed into human clinical trials for the treatment of cancer or other diseases [38]. These molecules usually have a unique head moiety that can form critical hydrogen bonds with residues of the BRD4 binding pocket.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of BRD4 Protein from a Marine-Derived Fungus Alternaria sp. NH-F6

Zhang

Zhou

2017

Marine Drugs

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Bromodomains (BRD) are readers of the epigenetic code that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Recently, bromodomain-containing proteins such as BRD4 have been demonstrated to be druggable through the discovery of potent inhibitors. These protein–protein interaction inhibitors have the potential to modulate multiple diseases by their profound anti-inflammatory and antiproliferative effects. In order to explore new BRD4 inhibitors as well as lead compounds for the development of new drugs, the secondary metabolites of Alternaria sp. NH-F6, a fungus isolated from deep-sea sediment samples, were analyzed systematically. Five new compounds including two new perylenequinones (1–2), one new alternaric acid (3), 2-(N-vinylacetamide)-4-hydroxymethyl-3-ene-butyrolactone (4), one new cerebroside (5), together with 19 known compounds (6–24) were isolated from the ethyl acetate extracts of this strain. Their structures were elucidated using nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses. Finally, all these compounds were evaluated for their inhibitory activity against BRD4 protein, and compound 2 exhibited a potent inhibition rate of 88.1% at a concentration of 10 µM. This research provides a new BRD4 inhibitor which may possess potential antitumoral, antiviral, or anti-inflammatory pharmaceutical values.

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Drug Discovery Targeting Bromodomain-Containing Protein 4

Cited by 256 publications

References 177 publications

Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation

Selective Antagonists of the Bronchiolar Epithelial NF-κB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation

The BRD3 ET domain recognizes a short peptide motif through a mechanism that is conserved across chromatin remodelers and transcriptional regulators

Inhibitors of BRD4 Protein from a Marine-Derived Fungus Alternaria sp. NH-F6

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