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https://www.readbyqxmd.com/read/27922200/a-fluorescence-lifetime-based-binding-assay-for-class-iia-histone-deacetylases
#1
Christian Meyners, Monique Mertens, Pablo Wessig, Franz-Josef Meyer-Almes
Class IIa HDACs show extremely low enzymatic activity and no commonly accepted endogenous substrate is known today. Increasing evidence suggests that these enzymes exert their effect rather through molecular recognition of acetylated proteins and recruiting other proteins like HDAC3 to the desired target location. Accordingly, class IIa HDACs like bromodomains have been suggested to act as "Readers" of acetyl marks, whereas enzymatically active HDACs from class I or IIb are called "Erasers" to highlight their capability to remove acetyl groups from acetylated histones or other proteins...
December 6, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27917784/suppression-of-bromodomain-containing-protein-4-by-shrna-a-new-approach-for-cancer-treatment
#2
Turan Kaya, Berke Kahraman, Nurgeldi Bazarov, Alperen S Toker, Ayse Celik, Sadik Cigdem, Esra Gunduz
PURPOSE: MYC is a transcription factor coding gene that is believed to control 15% of the genes in the entire human genome. The central role of c-MYC in cancer pathogenesis makes it a major therapeutic target in field of anticancer agent development. METHODS: We targeted the acetyl-lysine binding modules or bromodomains, which are associated with c-MYC transcriptional activation. RESULTS: Sequence specific inhibition of BET bromodomains with small hairpin RNAs (shRNAs) resulted in cessation of cellular proliferation in different cancer cell lines...
December 1, 2016: Clinical and Investigative Medicine. Médecine Clinique et Experimentale
https://www.readbyqxmd.com/read/27911230/bromodomain-inhibitors-and-cancer-therapy-from-structures-to-applications
#3
Montserrat Pérez-Salvia, Manel Esteller
Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are "writers", "erasers", or "readers" of histone modification marks are common. Bromodomains are "readers" that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains...
December 2, 2016: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/27909334/emerging-epigenetic-therapies-in-neuroscience-focus-on-bromodomain-containing-drug-targets
#4
Claes Wahlestedt
No abstract text is available yet for this article.
January 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27907905/association-of-high-microvessel-%C3%AE-v%C3%AE-3-and-low-pten-with-poor-outcome-in-stage-3-neuroblastoma-rationale-for-using-first-in-class-dual-pi3k-brd4-inhibitor-sf1126
#5
Anat Erdreich-Epstein, Alok R Singh, Shweta Joshi, Francisco M Vega, Pinzheng Guo, Jingying Xu, Susan Groshen, Wei Ye, Melissa Millard, Mihaela Campan, Guillermo Morales, Joseph R Garlich, Peter W Laird, Robert C Seeger, Hiroyuki Shimada, Donald L Durden
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αvβ3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αvβ3 was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in αvβ3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry)...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27904522/inducing-apolipoprotein-a-i-synthesis-to-reduce-cardiovascular-risk-from-assert-to-sustain-and-beyond
#6
Belinda A Di Bartolo, Daniel J Scherer, Stephen J Nicholls
Increasing attention has focused on efforts to promote the biological activities of high-density lipoproteins (HDL) in order to reduce cardiovascular risk. Targeting apolipoprotein A-I (apoA-I), the major protein carried on HDL particles, represents an attractive approach to promoting HDL by virtue of its ability to increase endogenous synthesis of functional HDL particles. A number of pharmacological strategies that target apoA-I, including upregulation of its production with the bromodomain and extraterminal (BET) protein inhibitor RVX-208, development of short peptide sequences that mimic its action, and administration as a component of reconstituted HDL particles, have undergone clinical development...
December 1, 2016: Archives of Medical Science: AMS
https://www.readbyqxmd.com/read/27903752/hexim1-as-a-robust-pharmacodynamic-marker-for-monitoring-target-engagement-of-bet-family-bromodomain-inhibitors-in-tumors-and-surrogate-tissues
#7
Xiaoyu Lin, Xiaoli Huang, Tamar Uziel, Paul Hessler, Daniel H Albert, Lisa A Roberts-Rapp, Keith F McDaniel, Warren M Kati, Yu Shen
An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET bromodomain inhibitor OTX015 using literature-described putative pharmacodynamic (PD) markers such as c-Myc, BRD2, etc. failed to detect PD marker responses in AML patients treated at active dose and those with clinical responses. Here we report the identification and characterization of HEXIM1 and other genes as robust PD markers for BET inhibitors...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#8
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27900832/bromodomain-and-extraterminal-protein-inhibitors-in-pediatrics-a-review-of-the-literature
#9
REVIEW
Irene Jiménez, André Baruchel, François Doz, Johannes Schulte
The last few years have seen the identification of pharmacologic approaches to target bromodomain and extraterminal (BET) proteins for cancer treatment. These proteins have an essential role in gene transcription regulation by binding acetylated lysine residues on histone tails, activating gene transcription. BET inhibitors have been tested in preclinical models including pediatric malignancies and several adult clinical trials are ongoing. Since the development of new drugs in pediatric cancer has long lagged behind programs for adults, the aim of this review is to show the importance of these therapies in pediatric malignancies to support their development in pediatric oncology/hematology...
November 30, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27890933/preclinical-activity-of-cpi-0610-a-novel-small-molecule-bromodomain-and-extra-terminal-protein-inhibitor-in-the-therapy-of-multiple-myeloma
#10
K T Siu, J Ramachandran, A J Yee, H Eda, L Santo, C Panaroni, J A Mertz, R J Sims, M R Cooper, N Raje
Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the anti-tumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing Phase I clinical testing, in multiple myeloma (MM)...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27890782/bromodomain-histone-readers-and-cancer
#11
REVIEW
Abhinav K Jain, Michelle C Barton
Lysine acetylation of histone proteins is a fundamental post-translational modification that regulates chromatin structure and plays an important role in gene transcription. Aberrant levels of histone lysine acetylation are associated with the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are structurally conserved modules present in transcription-associated proteins that are termed "reader" proteins. Bromodomain-containing reader proteins are part of multi-protein complexes that regulate transcription programs, often associated with profound phenotypic changes...
November 24, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27865874/bromodomain-containing-protein-2-induces-insulin-resistance-via-the-mtor-akt-signaling-pathway-and-an-inflammatory-response-in-adipose-tissue
#12
Ruixin Sun, Yi Wu, Weihua Hou, Zujun Sun, Yuxiong Wang, Huanhuan Wei, Wei Mo, Min Yu
Insulin resistance is a major metabolic abnormality in a large majority of patients with type II diabetes. Bromodomain-containing protein 2 (Brd2), a transcriptional co-activator/co-repressor with switch mating type/sucrose non-fermenting (SWI/SNF)-like functions that regulates chromatin, suppresses adipocyte differentiation and regulates pancreatic β-cell biology. However, the effects of Brd2 on insulin resistance remain unknown. Here, overexpression of Brd2 in white adipose tissue of wild-type (WT) mice led to insulin resistance...
November 16, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27864512/epstein-barr-virus-super-enhancer-ernas-are-essential-for-myc-oncogene-expression-and-lymphoblast-proliferation
#13
Jun Liang, Hufeng Zhou, Catherine Gerdt, Min Tan, Tyler Colson, Kenneth M Kaye, Elliott Kieff, Bo Zhao
Epstein-Barr virus (EBV) super-enhancers (ESEs) are essential for lymphoblastoid cell (LCL) growth and survival. Reanalyses of LCL global run-on sequencing (Gro-seq) data found abundant enhancer RNAs (eRNAs) being transcribed at ESEs. Inactivation of ESE components, EBV nuclear antigen 2 (EBNA2) and bromodomain-containing protein 4 (BRD4), significantly decreased eRNAs at ESEs -428 and -525 kb upstream of the MYC oncogene transcription start site (TSS). shRNA knockdown of the MYC -428 and -525 ESE eRNA caused LCL growth arrest and reduced cell growth...
November 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27864418/ampk-ulk1-mediated-autophagy-confers-resistance-to-bet-inhibitor-jq1-in-acute-myeloid-leukemia-stem-cells
#14
Ji Eun Jang, Ju In Eom, Hoi Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
PURPOSE: Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. EXPERIMENTAL DESIGN: We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+)CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations...
November 18, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27863698/striatal-h3k27-acetylation-linked-to-glutamatergic-gene-dysregulation-in-human-heroin-abusers-holds-promise-as-therapeutic-target
#15
Gabor Egervari, Joseph Landry, James Callens, John F Fullard, Panos Roussos, Eva Keller, Yasmin L Hurd
BACKGROUND: Opiate abuse and overdose reached epidemic levels in the United States. However, despite significant advances in animal and in vitro models, little knowledge has been directly accrued regarding the neurobiology of the opiate-addicted human brain. METHODS: We used postmortem human brain specimens from a homogeneous European Caucasian population of heroin users for transcriptional and epigenetic profiling, as well as direct assessment of chromatin accessibility in the striatum, a brain region central to reward and emotion...
September 28, 2016: Biological Psychiatry
https://www.readbyqxmd.com/read/27862999/assessment-of-bromodomain-target-engagement-by-a-series-of-bi2536-analogues-with-miniaturized-bet-bret
#16
Luke W Koblan, Dennis L Buckley, Christopher J Ott, Mark E Fitzgerald, Stuart W J Ember, Jin-Yi Zhu, Shuai Liu, Justin M Roberts, David Remillard, Sarah Vittori, Wei Zhang, Ernst Schonbrunn, James E Bradner
Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27858214/synthesis-and-biological-evaluation-of-n-3-oxo-3-4-dihydro-2h-benzo-b-1-4-oxazin-7-yl-benzenesulfonamide-derivatives-as-new-bet-bromodomain-inhibitors-for-anti-hematologic-malignancies-activities
#17
Li Liu, Yongxia Zhu, Zhihao Liu, Tinghong Ye, Weiqiong Zuo, Cuiting Peng, Kunjie Xiao, Ningyu Wang, Luoting Yu
The bromodomain and extra-terminal proteins (BETs), in particular BRD4, has been reported to play important roles in cancer, inflammation, obesity, cardiovascular disease, and neurological disorders. In this paper, a series of benzomorpholinone derivatives were synthesized and biologically evaluated as BETs inhibitors. Detailed structure-activity relationship studies led to the discovery of several new potent compounds, of which 15h and 15i displayed [Formula: see text] values of 2.8 and 4.5 [Formula: see text] against BRD4 (D1), respectively, and showed good anti-proliferation activities against four hematologic malignancies cell lines at low-micromolar concentrations, including MV4-11, OCI-LY10, Pfeifer, and Su-DHL-6 cells...
November 17, 2016: Molecular Diversity
https://www.readbyqxmd.com/read/27846392/a-druggable-tcf4-and-brd4-dependent-transcriptional-network-sustains-malignancy-in-blastic-plasmacytoid-dendritic-cell-neoplasm
#18
Michele Ceribelli, Zhiying Esther Hou, Priscilla N Kelly, Da Wei Huang, George Wright, Karthik Ganapathi, Moses O Evbuomwan, Stefania Pittaluga, Arthur L Shaffer, Guido Marcucci, Stephen J Forman, Wenming Xiao, Rajarshi Guha, Xiaohu Zhang, Marc Ferrer, Laurence Chaperot, Joel Plumas, Elaine S Jaffe, Craig J Thomas, Boris Reizis, Louis M Staudt
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#19
REVIEW
Yasushi Taniguchi
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code...
November 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27821592/bromodomain-and-extra-terminal-proteins-bet-inhibitors-suppress-chondrocyte-differentiation-and-restrain-bone-growth
#20
Ningning Niu, Rui Shao, Guang Yan, Weiguo Zou
Small-molecule inhibitors for bromodomain and extra-terminal proteins (BET) have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line, ATDC5, in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of chondrocyte...
November 7, 2016: Journal of Biological Chemistry
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