Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.
Probability-based protein identification by searching sequence databases using mass spectrometry data
The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p
Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein.
Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes
How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers
Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides
Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery
Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors
Bromodomain-Containing Protein 4: A Dynamic Regulator of Breast Cancer Metastasis through Modulation of the Extracellular Matrix
BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models
Alterations in brain-derived neurotrophic factor in the mouse hippocampus following acute but not repeated benzodiazepine treatment
High-throughput sperm differential proteomics suggests that epigenetic alterations contribute to failed assisted reproduction
Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes
Phenotypic screening and fragment-based approaches to the discovery of small-molecule bromodomain ligands
Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives
BET protein inhibition mitigates acute myocardial infarction damage in rats via the TLR4/TRAF6/NF-κB pathway
New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition
BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7
A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications
Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice
Discovery of CREBBP Bromodomain Inhibitors by High-Throughput Docking and Hit Optimization Guided by Molecular Dynamics
A loss of function screen of identified genome-wide association study Loci reveals new genes controlling hematopoiesis
Development of neurodevelopmental disorders: a regulatory mechanism involving bromodomain-containing proteins
Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology
BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells
Dual Kinase-Bromodomain Inhibitors in Anticancer Drug Discovery: A Structural and Pharmacological Perspective
Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4
Link Between ER-Stress, PPAR-Alpha Activation, and BET Inhibition in Relation to Apolipoprotein A-I Transcription in HepG2 Cells
In silico design and bioevaluation of selective benzotriazepine BRD4 inhibitors with potent antiosteoclastogenic activity
Design, synthesis and biological evaluation of 7-methylimidazo[1,5-a]pyrazin-8(7H)-one derivatives as BRD4 inhibitors
Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach
Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors
Bromodomain-containing protein 4-independent transcriptional activation by autoimmune regulator (AIRE) and NF-κB
Synergistic in-vitro effects of combining an antiglycolytic, 3-bromopyruvate, and a bromodomain-4 inhibitor on U937 myeloid leukemia cells
Deciphering the mechanisms of selective inhibition for the tandem BD1/BD2 in the BET-bromodomain family
Stimulation of Hepatic Apolipoprotein A-I Production by Novel Thieno-Triazolodiazepines: Roles of the Classical Benzodiazepine Receptor, PAF Receptor, and Bromodomain Binding
A Suite of "Minimalist" Photo-Crosslinkers for Live-Cell Imaging and Chemical Proteomics: Case Study with BRD4 Inhibitors
Tandemly Integrated HPV16 Can Form a Brd4-Dependent Super-Enhancer-Like Element That Drives Transcription of Viral Oncogenes
Computational study on the selective inhibition mechanism of MS402 to the first and second bromodomains of BRD4
I-BET151 suppresses osteoclast formation and inflammatory cytokines secretion by targetting BRD4 in multiple myeloma
BET bromodomain proteins mediate downstream signaling events following growth factor stimulation in human lung fibroblasts and are involved in bleomycin-induced pulmonary fibrosis
Chemical Epigenetics: The Impact of Chemical and Chemical Biology Techniques on Bromodomain Target Validation
In silico design and molecular basis for the selectivity of Olinone toward the first over the second bromodomain of BRD4.
An Adaptive Physiologically Based Pharmacokinetic-Driven Design to Investigate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of Molibresib (GSK525762) in Healthy Female Volunteers
Different orientations of low-molecular-weight fragments in the binding pocket of a BRD4 bromodomain
Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites
Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery
Binding Assays for Bromodomain Proteins: Their Utility in Drug Discovery in Oncology and Inflammatory Disease
Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma
Search for Natural Compounds That Increase Apolipoprotein A-I Transcription in HepG2 Cells: Specific Attention for BRD4 Inhibitors
Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
Unravelling novel congeners from acetyllysine mimicking ligand targeting a lysine acetyltransferase PCAF bromodomain
Brd/BET Proteins Influence the Genome-Wide Localization of the Kaposi's Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus Major Latency Proteins
The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer
Selective inhibition mechanism of nitroxoline to the BET family: Insight from molecular simulations.
Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors.
Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation
BRD4 methylation by the methyltransferase SETD6 regulates selective transcription to control mRNA translation.
Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.
STING Receptor Agonists
Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.
Chronic Fatigue Syndrome
Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.
Spatio-Temporal Regulation of DNA Repair
DNA repair is a complex process regulated by several different classes of enzymes, including ligases, endonucleases, and polymerases. This feed focuses on the spatial and temporal regulation that accompanies DNA damage signaling and repair enzymes and processes.
Glut1 deficiency, an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier, is characterized by mental and motor developmental delays and infantile seizures. Follow the latest research on Glut1 deficiency with this feed.
Hereditary Sensory Autonomic Neuropathy
Hereditary Sensory Autonomic Neuropathies are a group of inherited neurodegenerative disorders characterized clinically by loss of sensation and autonomic dysfunction. Here is the latest research on these neuropathies.
Separation anxiety is a type of anxiety disorder that involves excessive distress and anxiety with separation. This may include separation from places or people to which they have a strong emotional connection with. It often affects children more than adults. Here is the latest research on separation anxiety.
Neural Activity: Imaging
Imaging of neural activity in vivo has developed rapidly recently with the advancement of fluorescence microscopy, including new applications using miniaturized microscopes (miniscopes). This feed follows the progress in this growing field.
Applications of Molecular Barcoding
The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.