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Bradner, j

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https://www.readbyqxmd.com/read/27862999/assessment-of-bromodomain-target-engagement-by-a-series-of-bi2536-analogues-with-miniaturized-bet-bret
#1
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/27774131/development-of-a-potent-and-selective-hdac8-inhibitor
#2
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
https://www.readbyqxmd.com/read/27626654/bet-bromodomain-inhibition-promotes-anti-tumor-immunity-by-suppressing-pd-l1-expression
#3
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
https://www.readbyqxmd.com/read/27612420/atad2-is-an-epigenetic-reader-of-newly-synthesized-histone-marks-during-dna-replication
#4
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
https://www.readbyqxmd.com/read/27590350/multi-focal-control-of-mitochondrial-gene-expression-by-oncogenic-myc-provides-potential-therapeutic-targets-in-cancer
#5
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
https://www.readbyqxmd.com/read/27535106/targeting-chromatin-regulators-inhibits-leukemogenic-gene-expression-in-npm1-mutant-leukemia
#6
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
https://www.readbyqxmd.com/read/27531676/gene-expression-based-discovery-of-atovaquone-as-a-stat3-inhibitor-and-anti-cancer-agent
#7
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
https://www.readbyqxmd.com/read/27498870/high-resolution-mapping-of-rna-polymerases-identifies-mechanisms-of-sensitivity-and-resistance-to-bet-inhibitors-in-t-8-21-aml
#8
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
https://www.readbyqxmd.com/read/27406984/bet-inhibition-induces-apoptosis-in-aggressive-b-cell-lymphoma-via-epigenetic-regulation-of-bcl-2-family-members
#9
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
https://www.readbyqxmd.com/read/27292631/pi3k-akt-signaling-regulates-h3k4-methylation-in-breast-cancer
#10
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
https://www.readbyqxmd.com/read/27281427/erratum-community-crystal-gazing
#11
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
https://www.readbyqxmd.com/read/26963550/community-crystal-gazing
#12
Anu Acharya, Kate Bingham, Jay Bradner, Wylie Burke, R Alta Charo, Joel Cherry, André Choulika, Tony Coles, Robert Cook-Deegan, Stanley T Crooke, 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.
March 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/26843070/models-of-human-core-transcriptional-regulatory-circuitries
#13
Violaine Saint-André, Alexander J Federation, Charles Y Lin, Brian J Abraham, Jessica Reddy, Tong Ihn Lee, James E Bradner, Richard A Young
A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate their own gene expression, thus forming an interconnected auto-regulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping...
March 2016: Genome Research
https://www.readbyqxmd.com/read/26829751/myb-qki-rearrangements-in-angiocentric-glioma-drive-tumorigenicity-through-a-tripartite-mechanism
#14
Pratiti Bandopadhayay, Lori A Ramkissoon, Payal Jain, Guillaume Bergthold, Jeremiah Wala, Rhamy Zeid, Steven E Schumacher, Laura Urbanski, Ryan O'Rourke, William J Gibson, Kristine Pelton, Shakti H Ramkissoon, Harry J Han, Yuankun Zhu, Namrata Choudhari, Amanda Silva, Katie Boucher, Rosemary E Henn, Yun Jee Kang, David Knoff, Brenton R Paolella, Adrianne Gladden-Young, Pascale Varlet, Melanie Pages, Peleg M Horowitz, Alexander Federation, Hayley Malkin, Adam A Tracy, Sara Seepo, Matthew Ducar, Paul Van Hummelen, Mariarita Santi, Anna Maria Buccoliero, Mirko Scagnet, Daniel C Bowers, Caterina Giannini, Stephanie Puget, Cynthia Hawkins, Uri Tabori, Almos Klekner, Laszlo Bognar, Peter C Burger, Charles Eberhart, Fausto J Rodriguez, D Ashley Hill, Sabine Mueller, Daphne A Haas-Kogan, Joanna J Phillips, Sandro Santagata, Charles D Stiles, James E Bradner, Nada Jabado, Alon Goren, Jacques Grill, Azra H Ligon, Liliana Goumnerova, Angela J Waanders, Phillip B Storm, Mark W Kieran, Keith L Ligon, Rameen Beroukhim, Adam C Resnick
Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI...
March 2016: Nature Genetics
https://www.readbyqxmd.com/read/26829750/an-oncogenic-myb-feedback-loop-drives-alternate-cell-fates-in-adenoid-cystic-carcinoma
#15
Yotam Drier, Matthew J Cotton, Kaylyn E Williamson, Shawn M Gillespie, Russell J H Ryan, Michael J Kluk, Christopher D Carey, Scott J Rodig, Lynette M Sholl, Amir H Afrogheh, William C Faquin, Lurdes Queimado, Jun Qi, Michael J Wick, Adel K El-Naggar, James E Bradner, Christopher A Moskaluk, Jon C Aster, Birgit Knoechel, Bradley E Bernstein
Translocation events are frequent in cancer and may create chimeric fusions or 'regulatory rearrangements' that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps highlight distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter...
March 2016: Nature Genetics
https://www.readbyqxmd.com/read/26814967/active-medulloblastoma-enhancers-reveal-subgroup-specific-cellular-origins
#16
Charles Y Lin, Serap Erkek, Yiai Tong, Linlin Yin, Alexander J Federation, Marc Zapatka, Parthiv Haldipur, Daisuke Kawauchi, Thomas Risch, Hans-Jörg Warnatz, Barbara C Worst, Bensheng Ju, Brent A Orr, Rhamy Zeid, Donald R Polaski, Maia Segura-Wang, Sebastian M Waszak, David T W Jones, Marcel Kool, Volker Hovestadt, Ivo Buchhalter, Laura Sieber, Pascal Johann, Lukas Chavez, Stefan Gröschel, Marina Ryzhova, Andrey Korshunov, Wenbiao Chen, Victor V Chizhikov, Kathleen J Millen, Vyacheslav Amstislavskiy, Hans Lehrach, Marie-Laure Yaspo, Roland Eils, Peter Lichter, Jan O Korbel, Stefan M Pfister, James E Bradner, Paul A Northcott
Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens...
February 4, 2016: Nature
https://www.readbyqxmd.com/read/26482930/harnessing-connectivity-in-a-large-scale-small-molecule-sensitivity-dataset
#17
Brinton Seashore-Ludlow, Matthew G Rees, Jaime H Cheah, Murat Cokol, Edmund V Price, Matthew E Coletti, Victor Jones, Nicole E Bodycombe, Christian K Soule, Joshua Gould, Benjamin Alexander, Ava Li, Philip Montgomery, Mathias J Wawer, Nurdan Kuru, Joanne D Kotz, C Suk-Yee Hon, Benito Munoz, Ted Liefeld, Vlado Dančík, Joshua A Bittker, Michelle Palmer, James E Bradner, Alykhan F Shamji, Paul A Clemons, Stuart L Schreiber
UNLABELLED: Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset...
November 2015: Cancer Discovery
https://www.readbyqxmd.com/read/26440387/characteristics-of-youth-presenting-for-weight-management-retrospective-national-data-from-the-power-study-group
#18
Carolyn Bradner Jasik, Eileen C King, Erinn Rhodes, Brooke Sweeney, Michele Mietus-Snyder, H Mollie Grow, J Mitchell Harris, Lynne Lostocco, Elizabeth Estrada, Katie Boyle, Jared M Tucker, Ihuoma U Eneli, Susan J Woolford, George Datto, William Stratbucker, Shelley Kirk
BACKGROUND: There are no existing multisite national data on obese youth presenting for pediatric weight management. The primary aim was to describe BMI status and comorbidities among youth with obesity presenting for pediatric weight management (PWM) at programs within the Pediatric Obesity Weight Evaluation Registry (POWER). METHODS: Data were collected from 2009-2010 among 6737 obese patients ages 2-17. Patients were classified in three groups by BMI (kg/m(2)) cutoffs and percent of the 95th percentile for BMI: (1) obesity; (2) severe obesity class 2; and (3) severe obesity class 3...
October 2015: Childhood Obesity
https://www.readbyqxmd.com/read/26438361/dose-dependent-role-of-the-cohesin-complex-in-normal-and-malignant-hematopoiesis
#19
Aaron D Viny, Christopher J Ott, Barbara Spitzer, Martin Rivas, Cem Meydan, Efthymia Papalexi, Dana Yelin, Kaitlyn Shank, Jaime Reyes, April Chiu, Yevgeniy Romin, Vitaly Boyko, Swapna Thota, Jaroslaw P Maciejewski, Ari Melnick, James E Bradner, Ross L Levine
Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function...
October 19, 2015: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/26390243/combined-inhibition-of-bet-family-proteins-and-histone-deacetylases-as-a-potential-epigenetics-based-therapy-for-pancreatic-ductal-adenocarcinoma
#20
Pawel K Mazur, Alexander Herner, Stephano S Mello, Matthias Wirth, Simone Hausmann, Francisco J Sánchez-Rivera, Shane M Lofgren, Timo Kuschma, Stephan A Hahn, Deepak Vangala, Marija Trajkovic-Arsic, Aayush Gupta, Irina Heid, Peter B Noël, Rickmer Braren, Mert Erkan, Jörg Kleeff, Bence Sipos, Leanne C Sayles, Mathias Heikenwalder, Elisabeth Heßmann, Volker Ellenrieder, Irene Esposito, Tyler Jacks, James E Bradner, Purvesh Khatri, E Alejandro Sweet-Cordero, Laura D Attardi, Roland M Schmid, Guenter Schneider, Julien Sage, Jens T Siveke
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC...
October 2015: Nature Medicine
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