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james bradner

Minoru Tanaka, Justin M Roberts, Hyuk-Soo Seo, Amanda Souza, Joshiawa Paulk, Thomas G Scott, Stephen L DeAngelo, Sirano Dhe-Paganon, James E Bradner
Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors...
October 24, 2016: Nature Chemical Biology
Oscar J Ingham, Ronald M Paranal, William B Smith, Randolph A Escobar, Han Yueh, Tracy Snyder, John A Porco, James E Bradner, Aaron B Beeler
A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.
October 13, 2016: ACS Medicinal Chemistry Letters
Marc Baud'huin, François Lamoureux, Camille Jacques, Lidia Rodriguez Calleja, Thibaut Quillard, Céline Charrier, Jérome Amiaud, Martine Berreur, Bénédicte Brounais-LeRoyer, Robert Owen, Gwendolen C Reilly, James E Bradner, Dominique Heymann, Benjamin Ory
Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro...
September 23, 2016: Bone
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...
September 20, 2016: Journal of Biological Chemistry
Huafeng Xie, Cong Peng, Jialiang Huang, Bin E Li, Woojin Kim, Elenoe C Smith, Yuko Fujiwara, Jun Qi, Giulia Cheloni, Partha P Das, Minh Nguyen, Shaoguang Li, James E Bradner, Stuart H Orkin
Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia initiating cells (LICs) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs, required for colony formation, and survival and cell cycle progression of CML cell lines. A critical role for Ezh2 is supported by genetic studies in a mouse CML model...
September 14, 2016: Cancer Discovery
Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R Rutkowski, Benjamin G Bitler, Michael J Allegrezza, Yuhki Yokoyama, Andrew V Kossenkov, James E Bradner, Jose R Conejo-Garcia, Rugang Zhang
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells...
September 13, 2016: Cell Reports
Seong Joo Koo, Amaury E Fernández-Montalván, Volker Badock, Christopher J Ott, Simon J Holton, Oliver von Ahsen, Joern Toedling, Sarah Vittori, James E Bradner, Mátyás Gorjánácz
ATAD2 (ATPase family AAA domain-containing protein 2) is a chromatin regulator harboring an AAA+ ATPase domain and a bromodomain, previously proposed to function as an oncogenic transcription co-factor. Here we suggest that ATAD2 is also required for DNA replication. ATAD2 is co-expressed with genes involved in DNA replication in various cancer types and predominantly expressed in S phase cells where it localized on nascent chromatin (replication sites). Our extensive biochemical and cellular analyses revealed that ATAD2 is recruited to replication sites through a direct interaction with di-acetylated histone H4 at K5 and K12, indicative of newly synthesized histones during replication-coupled chromatin reassembly...
September 6, 2016: Oncotarget
Amanda R Oran, Clare M Adams, Xiao-Yong Zhang, Victoria J Gennaro, Harla K Pfeiffer, Hestia S Mellert, Hans E Seidel, Kirsten Mascioli, Jordan Kaplan, Mahmoud R Gaballa, Chen Shen, Isidore Rigoutsos, Michael P King, Justin L Cotney, Jamie J Arnold, Suresh D Sharma, Ubaldo E Martinez-Outschoorn, Christopher R Vakoc, Lewis A Chodosh, James E Thompson, James E Bradner, Craig E Cameron, Gerald S Shadel, Christine M Eischen, Steven B McMahon
Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production...
August 31, 2016: Oncotarget
Michael W M Kühn, Evelyn Song, Zhaohui Feng, Amit Sinha, Chun-Wei Chen, Aniruddha J Deshpande, Monica Cusan, Noushin Farnoud, Annalisa Mupo, Carolyn Grove, Richard Koche, James E Bradner, Elisa de Stanchina, George S Vassiliou, Takayuki Hoshii, Scott A Armstrong
: Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1(mut)) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1(mut) AML...
October 2016: Cancer Discovery
Michael Xiang, Haesook Kim, Vincent T Ho, Sarah R Walker, Michal Bar-Natan, Melodi Anahtar, Suhu Liu, Patricia A Toniolo, Yasmin Kroll, Nichole Jones, Zachary T Giaccone, Lisa N Heppler, Darwin Q Ye, Jason J Marineau, Daniel Shaw, James E Bradner, Traci Blonquist, Donna Neuberg, Claudio Hetz, Richard M Stone, Robert J Soiffer, David A Frank
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically-available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron™), an FDA-approved anti-microbial, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells...
August 16, 2016: Blood
Nicole G Chau, Shelley Hurwitz, Chelsey M Mitchell, Alexandra Aserlind, Noam Grunfeld, Leah Kaplan, Peter Hsi, Daniel E Bauer, Christopher S Lathan, Carlos Rodriguez-Galindo, Roy B Tishler, Robert I Haddad, Stephen E Sallan, James E Bradner, Christopher A French
BACKGROUND: NUT midline carcinoma is a rare and aggressive genetically characterized subtype of squamous cell carcinoma frequently arising from the head and neck. The characteristics and optimal management of head and neck NUT midline carcinoma (HNNMC) are unclear. METHODS: A retrospective review of all known cases of HNNMC in the International NUT Midline Carcinoma Registry as of December 31, 2014, was performed. Forty-eight consecutive patients were treated from 1993 to 2014, and clinicopathologic variables and outcomes for 40 patients were available for analyses; they composed the largest HNNMC cohort studied to date...
August 10, 2016: Cancer
Yue Zhao, Qi Liu, Pankaj Acharya, Kristy R Stengel, Quanhu Sheng, Xiaofan Zhou, Hojoong Kwak, Melissa A Fischer, James E Bradner, Stephen A Strickland, Sanjay R Mohan, Michael R Savona, Bryan J Venters, Ming-Ming Zhou, John T Lis, Scott W Hiebert
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML...
August 16, 2016: Cell Reports
Matthew S Stratton, Charles Y Lin, Priti Anand, Philip D Tatman, Bradley S Ferguson, Sean T Wickers, Amrut V Ambardekar, Carmen C Sucharov, James E Bradner, Saptarsi M Haldar, Timothy A McKinsey
BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for the regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3' UTR of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes...
August 2, 2016: Cell Reports
Anjali Mishra, Krista La Perle, Sonya Kwiatkowski, Laura A Sullivan, Gregory H Sams, Jessica Johns, Douglas P Curphey, Jing Wen, Kathleen McConnell, Jun Qi, Henry Wong, Giandomenico Russo, Jianying Zhang, Guido Marcucci, James E Bradner, Pierluigi Porcu, Michael A Caligiuri
UNLABELLED: Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage-dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15 Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm...
September 2016: Cancer Discovery
Simon J Hogg, Andrea Newbold, Stephin J Vervoort, Leonie A Cluse, Benjamin P Martin, Gareth P Gregory, Marcus Lefebure, Eva Vidacs, Richard W Tothill, James E Bradner, Jake Shortt, Ricky W Johnstone
Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression...
September 2016: Molecular Cancer Therapeutics
Peng Wang, Marcus E Farmer, Xing Huo, Pankaj Jain, Peng-Xiang Shen, Mette Ishoey, James E Bradner, Steven R Wisniewski, Martin D Eastgate, Jin-Quan Yu
Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C-H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C-H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C-H arylation of a lenalidomide derivative...
July 27, 2016: Journal of the American Chemical Society
Kathleen P Tebb, Rebecca K Erenrich, Carolyn Bradner Jasik, Mark S Berna, James C Lester, Elizabeth M Ozer
BACKGROUND: Alcohol use and binge drinking among adolescents and young adults remain frequent causes of preventable injuries, disease, and death, and there has been growing attention to computer-based modes of intervention delivery to prevent/reduce alcohol use. Research suggests that health interventions grounded in established theory are more effective than those with no theoretical basis. The goal of this study was to conduct a literature review of computer-based interventions (CBIs) designed to address alcohol use among adolescents and young adults (aged 12-21 years) and examine the extent to which CBIs use theories of behavior change in their development and evaluations...
2016: BMC Public Health
Haikuo Zhang, Jun Qi, Jaime M Reyes, Lewyn Li, Prakash K Rao, Fugen Li, Charles Y Lin, Jennifer A Perry, Matthew A Lawlor, Alexander Federation, Thomas De Raedt, Yvonne Y Li, Yan Liu, Melissa A Duarte, Yanxi Zhang, Grit S Herter-Sprie, Eiki Kikuchi, Julian Carretero, Charles M Perou, Jacob B Reibel, Joshiawa Paulk, Roderick T Bronson, Hideo Watanabe, Christine Fillmore Brainson, Carla F Kim, Peter S Hammerman, Myles Brown, Karen Cichowski, Henry Long, James E Bradner, Kwok-Kin Wong
UNLABELLED: As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma...
September 2016: Cancer Discovery
Jennifer M Spangle, Koen M Dreijerink, Anna C Groner, Hailing Cheng, Carolynn E Ohlson, Jaime Reyes, Charles Y Lin, James Bradner, Jean J Zhao, Thomas M Roberts, Myles Brown
Post-translational histone H3 modifications regulate transcriptional competence. The mechanisms by which the epigenome is regulated in response to oncogenic signaling remain unclear. Here we show that H3K4me3 is increased in breast tumors driven by an activated PIK3CA allele and that inhibition of PI3K/AKT signaling reduces promoter-associated H3K4me3 in human breast cancer cells. We show that the H3K4 demethylase KDM5A is an AKT target and that phosphorylation of KDM5A regulates its nuclear localization and promoter occupancy...
June 21, 2016: Cell Reports
Anu Acharya, Kate Bingham, Jay Bradner, Wylie Burke, R Alta Charo, Joel Cherry, André Choulika, Tony Coles, Robert Cook-Deegan, Stanley T Crook, Emilia Díaz, Brent Erickson, L Val Giddings, Sebastian Eriksson Giwa, James C Greenwood, Vishal Gulati, Sam Hall, John Harris, Jamie Heywood, Colin Hill, Jeremy Levin, Adina Mangubat, John Maraganore, Giovanni Mariggi, Barbara J Mazur, Amy L McGuire, Nathalie Moll, Jonathan Moreno, Gail Naughton, Lita Nelsen, Jane Osbourn, Daniel Perez, John Reed, Eric Schmidt, Vicki Seyfert-Margolis, Paul Stoffels, Jørgen Thorball, Tara O'Toole, Indrek Vainu, Sander van Deventer, Elias Zerhouni, Daphne Zohar
No abstract text is available yet for this article.
June 9, 2016: Nature Biotechnology
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