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Myc AND BRD4

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https://www.readbyqxmd.com/read/27864512/epstein-barr-virus-super-enhancer-ernas-are-essential-for-myc-oncogene-expression-and-lymphoblast-proliferation
#1
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/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#2
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/27769357/clinical-trials-for-bet-inhibitors-run-ahead-of-the-science
#3
REVIEW
Guillaume Andrieu, Anna C Belkina, Gerald V Denis
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27732564/pharmacological-targeting-of-bet-proteins-inhibits-renal-fibroblast-activation-and-alleviates-renal-fibrosis
#4
Chongxiang Xiong, Monica V Masucci, Xiaoxu Zhou, Na Liu, Xiujuan Zang, Evelyn Tolbert, Ting C Zhao, Shougang Zhuang
Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively inhibit tumorgenesis and ameliorate pulmonary fibrosis by targeting bromodomain proteins that bind acetylated chromatin markers. However, their pharmacological effects in renal fibrosis remain unclear. In this study, we examined the effect of I-BET151, a selective and potent BET inhibitor, on renal fibroblast activation and renal fibrosis. In cultured renal interstitial fibroblasts, exposure of cells to I-BET151, or silencing of bromodoma in-containing protein 4 (Brd4), a key BET protein isoform, significantly reduced their activation as indicated by decreased expression of α-smooth muscle actin, collagen 1 and fibronectin...
October 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27707886/exploitation-of-castration-resistant-prostate-cancer-transcription-factor-dependencies-by-the-novel-bet-inhibitor-abbv-075
#5
Emily J Faivre, Denise Wilcox, Xiaoyu Lin, Paul Hessler, Maricel Torrent, Wei He, Tamar Uziel, Daniel H Albert, Keith McDaniel, Warren Kati, Yu Shen
: Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/super-enhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the Androgen Receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075...
October 5, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27682507/discovery-of-a-potent-and-selective-in-vivo-probe-gne-272-for-the-bromodomains-of-cbp-ep300
#6
Terry D Crawford, F Anthony Romero, Kwong Wah Lai, Vickie Tsui, Alexander M Taylor, Gladys de Leon Boenig, Cameron L Noland, Jeremy Murray, Justin Ly, Edna F Choo, Thomas L Hunsaker, Emily W Chan, Mark Merchant, Samir Kharbanda, Karen E Gascoigne, Susan Kaufman, Maureen H Beresini, Jiangpeng Liao, Wenfeng Liu, Kevin X Chen, Zhongguo Chen, Andrew R Conery, Alexandre Côté, Hariharan Jayaram, Ying Jiang, James R Kiefer, Tracy Kleinheinz, Yingjie Li, Jonathan Maher, Eneida Pardo, Florence Poy, Kerry L Spillane, Fei Wang, Jian Wang, Xiaocang Wei, Zhaowu Xu, Zhongya Xu, Ivana Yen, Laura Zawadzke, Xiaoyu Zhu, Steven Bellon, Richard Cummings, Andrea G Cochran, Brian K Albrecht, Steven Magnuson
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0...
September 28, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27650498/bromodomain-and-extraterminal-protein-inhibition-blocks-growth-of-triple-negative-breast-cancers-through-the-suppression-of-aurora-kinases
#7
Jennifer M Sahni, Sylvia S Gayle, Kristen L Weber Bonk, Leslie Cuellar Vite, Jennifer L Yori, Bryan Webb, Erika K Ramos, Darcie D Seachrist, Melissa D Landis, Jenny C Chang, James E Bradner, Ruth A Keri
Bromodomain and extraterminal (BET) proteins are epigenetic "readers" that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer, and BET protein inhibitors (BETi) are efficacious in many preclinical cancer models. However, the drivers of response to BETi vary depending on tumor type, and little is known regarding the target genes conveying BETi activity in triple-negative breast cancer (TNBC). Here, we show that BETi repress growth of multiple in vitro and in vivo models of TNBC by inducing two terminal responses: apoptosis and senescence...
November 4, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27573714/jq1-a-small-molecule-inhibitor-of-brd4-suppresses-cell-growth-and-invasion-in-oral-squamous-cell-carcinoma
#8
Limei Wang, Xiuyin Wu, Ping Huang, Zhijun Lv, Yuping Qi, Xiujuan Wei, Pishan Yang, Fenghe Zhang
The present study aimed to evaluate whether bromodomain 4 (BRD4) is expressed in Cal27 cells and to assess the effect of JQ1 on cell proliferation, apoptosis, invasion and BRD4, C-Myc and Twist expression in Cal27 cells. Immunofluorescence staining was used to determine whether BRD4 was expressed in Cal27 cells. Cell viability and proliferation were evaluated using CCK-8 assay. Flow cytometry was used to determine the apoptosis and cell cycle distribution. The cell invasion was evaluated using Transwell plate...
October 2016: Oncology Reports
https://www.readbyqxmd.com/read/27573426/azd5153-a-novel-bivalent-bet-bromodomain-inhibitor-highly-active-against-hematologic-malignancies
#9
Garrett W Rhyasen, Maureen Hattersley, Yi Yao, Austin Dulak, Wenxian Wang, Philip Petteruti, Ian Dale, Scott Boiko, Tony Cheung, Jingwen Zhang, Shenghua Wen, Lillian Castriotta, Deborah Lawson, Michael Collins, Larry Bao, Miika J Ahdesmaki, Graeme Walker, Greg O'Connor, Tammie Yeh, Alfred A Rabow, Jonathan Dry, Corinne Reimer, Paul Lyne, Gordon B Mills, Stephen Fawell, Michael J Waring, Michael Zinda, Edwin Clark, Huawei Chen
The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small-molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously...
August 29, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27572308/jq1-suppresses-tumor-growth-via-pten-pi3k-akt-pathway-in-endometrial-cancer
#10
Haifeng Qiu, Jing Li, Leslie H Clark, Amanda L Jackson, Lu Zhang, Hui Guo, Joshua E Kilgore, Paola A Gehrig, Chunxiao Zhou, Victoria L Bae-Jump
Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression...
August 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27531767/-effect-of-brd4-inhibitor-jq1-on-proliferation-inhibition-and-apotosis-induction-in-jurkat-cells
#11
Xiao-Xia Sun, Liang-Ming Ma, Tao Wang
OBJECTIVE: To investigate the effect and possible mechanism of bromo-domain inhibitors (JQ1) on proliferation inhibition and inducing apoptosis of acute T lymphocyte leukemia cell line (Jurkat) . METHODS: Jurkat cell line was treated by JQ1 at different concentrations. MTT was used to detect the cell proliferation inhibition rate. The flow cytometry with AnnexinV-FITC/PI fluorescence staining was used to detect the changes of apoptosis rate, and real-time fluorescent quantitative PCR was used to detect c-Myc/Notch1 gene expression levels...
August 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/27528113/optimization-of-a-series-of-bivalent-triazolopyridazine-based-bromodomain-and-extraterminal-inhibitors-the-discovery-of-3r-4-2-4-1-3-methoxy-1-2-4-triazolo-4-3-b-pyridazin-6-yl-4-piperidyl-phenoxy-ethyl-1-3-dimethyl-piperazin-2-one-azd5153
#12
Robert H Bradbury, Rowena Callis, Gregory R Carr, Huawei Chen, Edwin Clark, Lyman Feron, Steve Glossop, Mark A Graham, Maureen Hattersley, Chris Jones, Scott G Lamont, Gilles Ouvry, Anil Patel, Joe Patel, Alfred A Rabow, Craig A Roberts, Stephen Stokes, Natalie Stratton, Graeme E Walker, Lara Ward, David Whalley, David Whittaker, Gail Wrigley, Michael J Waring
Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153...
September 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27520485/epigenetic-blockade-of-neoplastic-transformation-by-bromodomain-and-extra-terminal-bet-domain-protein-inhibitor-jq-1
#13
Chengyue Zhang, Zheng-Yuan Su, Ling Wang, Limin Shu, Yuqing Yang, Yue Guo, Douglas Pung, Chas Bountra, Ah-Ng Kong
The neoplastic transformation of cells and inflammation are processes that contribute to tumor initiation. Recently, emerging evidence has suggested that epigenetic alterations are also implicated in the early stages of carcinogenesis. Therefore, potent small molecules targeting epigenetic regulators have been developed as novel cancer therapeutic and preventive strategies. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that play key roles at the interface between chromatin modification and transcriptional regulation...
October 1, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27496136/single-agent-and-synergistic-activity-of-the-first-in-class-dual-pi3k-brd4-inhibitor-sf1126-with-sorafenib-in-hepatocellular-carcinoma
#14
Alok R Singh, Shweta Joshi, Adam M Burgoyne, Jason K Sicklick, Sadakatsu Ikeda, Yuko Kono, Joseph R Garlich, Guillermo A Morales, Donald L Durden
Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI-3K/BRD4 inhibitors which can be used either alone or in combination with Sorafenib to treat patients with advanced HCC. Herein we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with Sorafenib inhibited proliferation, cell cycle, apoptosis and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep 3B, Hep G2, SK-Hep1 and Huh7 HCC cell lines...
August 5, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27443262/compensatory-rna-polymerase-2-loading-determines-the-efficacy-and-transcriptional-selectivity-of-jq1-in-myc-driven-tumors
#15
E Donato, O Croci, A Sabò, H Muller, M J Morelli, M Pelizzola, S Campaner
Inhibition of bromodomain and extraterminal motif (BET) proteins such as BRD4 bears great promise for cancer treatment and its efficacy has been frequently attributed to Myc downregulation. Here, we use B-cell tumors as a model to address the mechanism of action of JQ1, a widely used BET inhibitor. Although JQ1 led to widespread eviction of BRD4 from chromatin, its effect on gene transcription was limited to a restricted set of genes. This was unlinked to Myc downregulation or its chromatin association. Yet, JQ1-sensitive genes were enriched for Myc and E2F targets, were expressed at high levels, and showed high promoter occupancy by RNAPol2, BRD4, Myc and E2F...
July 22, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27388964/otx015-mk-8628-a-novel-bet-inhibitor-displays-in-vitro-and-in-vivo-antitumor-effects-alone-and-in-combination-with-conventional-therapies-in-glioblastoma-models
#16
Caroline Berenguer-Daizé, Lucile Astorgues-Xerri, Elodie Odore, Mylène Cayol, Esteban Cvitkovic, Kay Noel, Mohamed Bekradda, Sarah MacKenzie, Keyvan Rezai, François Lokiec, Maria E Riveiro, L'Houcine Ouafik
Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines...
November 1, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27159579/mapping-the-chemical-chromatin-reactivation-landscape-identifies-brd4-taf1-cross-talk
#17
Sara Sdelci, Charles-Hugues Lardeau, Cynthia Tallant, Freya Klepsch, Björn Klaiber, James Bennett, Philipp Rathert, Michael Schuster, Thomas Penz, Oleg Fedorov, Giulio Superti-Furga, Christoph Bock, Johannes Zuber, Kilian V M Huber, Stefan Knapp, Susanne Müller, Stefan Kubicek
Bromodomain-containing proteins of the BET family recognize histone lysine acetylation and mediate transcriptional activation of target genes such as the MYC oncogene. Pharmacological inhibitors of BET domains promise therapeutic benefits in a variety of cancers. We performed a high-diversity chemical compound screen for agents capable of modulating BRD4-dependent heterochromatization of a generic reporter in human cells. In addition to known and new compounds targeting BRD4, we identified small molecules that mimic BRD4 inhibition without direct engagement...
July 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27159561/brd4-is-a-histone-acetyltransferase-that-evicts-nucleosomes-from-chromatin
#18
Ballachanda N Devaiah, Chanelle Case-Borden, Anne Gegonne, Chih Hao Hsu, Qingrong Chen, Daoud Meerzaman, Anup Dey, Keiko Ozato, Dinah S Singer
Bromodomain protein 4 (BRD4) is a chromatin-binding protein implicated in cancer and autoimmune diseases that functions as a scaffold for transcription factors at promoters and super-enhancers. Although chromatin decompaction and transcriptional activation of target genes are associated with BRD4 binding, the mechanisms involved are unknown. We report that BRD4 is a histone acetyltransferase (HAT) that acetylates histones H3 and H4 with a pattern distinct from those of other HATs. Both mouse and human BRD4 have intrinsic HAT activity...
June 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27148573/complete-hematologic-response-of-early-t-cell-progenitor-acute-lymphoblastic-leukemia-to-the-%C3%AE-secretase-inhibitor-bms-906024-genetic-and-epigenetic-findings-in-an-outlier-case
#19
Birgit Knoechel, Ami Bhatt, Li Pan, Chandra S Pedamallu, Eric Severson, Alejandro Gutierrez, David M Dorfman, Frank C Kuo, Michael Kluk, Andrew L Kung, Patrick Zweidler-McKay, Matthew Meyerson, Stephen C Blacklow, Daniel J DeAngelo, Jon C Aster
Notch pathway antagonists such as γ-secretase inhibitors (GSIs) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole-exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A...
October 2015: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27081696/epigenetic-reader-brd4-inhibition-as-a-therapeutic-strategy-to-suppress-e2f2-cell-cycle-regulation-circuit-in-liver-cancer
#20
Seong Hwi Hong, Jung Woo Eun, Sung Kyung Choi, Qingyu Shen, Wahn Soo Choi, Jeung-Whan Han, Suk Woo Nam, Jueng Soo You
Deregulation of the epigenome component affects multiple pathways in the cancer phenotype since the epigenome acts at the pinnacle of the hierarchy of gene expression. Pioneering work over the past decades has highlighted that targeting enzymes or proteins involved in the epigenetic regulation is a valuable approach to cancer therapy. Very recent results demonstrated that inhibiting the epigenetic reader BRD4 has notable efficacy in diverse cancer types. We investigated the potential of BRD4 as a therapeutic target in liver malignancy...
May 31, 2016: Oncotarget
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