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https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#1
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28781076/epigenetic-reprogramming-of-lineage-committed-human-mammary-epithelial-cells-requires-dnmt3a-and-loss-of-dot1l
#2
Jerrica L Breindel, Adam Skibinski, Maja Sedic, Ania Wronski-Campos, Wenhui Zhou, Patricia J Keller, Joslyn Mills, James Bradner, Tamer Onder, Charlotte Kuperwasser
Organogenesis and tissue development occur through sequential stepwise processes leading to increased lineage restriction and loss of pluripotency. An exception to this appears in the adult human breast, where rare variant epithelial cells exhibit pluripotency and multilineage differentiation potential when removed from the signals of their native microenvironment. This phenomenon provides a unique opportunity to study mechanisms that lead to cellular reprogramming and lineage plasticity in real time. Here, we show that primary human mammary epithelial cells (HMECs) lose expression of differentiated mammary epithelial markers in a manner dependent on paracrine factors and epigenetic regulation...
July 25, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28696689/correction-to-bet-bromodomain-inhibitors-with-one-step-synthesis-discovered-from-virtual-screen
#3
Alex M Ayoub, Laura M L Hawk, Ryan J Herzig, Jiewei Jiang, Andrea J Wisniewski, Clifford T Gee, Peiliang Zhao, Jin-Yi Zhu, Norbert Berndt, Nana K Offei-Addo, Thomas G Scott, Jun Qi, James E Bradner, Timothy R Ward, Ernst Schönbrunn, Gunda I Georg, William C K Pomerantz
No abstract text is available yet for this article.
July 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28673542/bet-bromodomain-proteins-function-as-master-transcription-elongation-factors-independent-of-cdk9-recruitment
#4
Georg E Winter, Andreas Mayer, Dennis L Buckley, Michael A Erb, Justine E Roderick, Sarah Vittori, Jaime M Reyes, Julia di Iulio, Amanda Souza, Christopher J Ott, Justin M Roberts, Rhamy Zeid, Thomas G Scott, Joshiawa Paulk, Kate Lachance, Calla M Olson, Shiva Dastjerdi, Sophie Bauer, Charles Y Lin, Nathanael S Gray, Michelle A Kelliher, L Stirling Churchman, James E Bradner
Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation...
July 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28638377/a-novel-bromodomain-inhibitor-reverses-hiv-1-latency-through-specific-binding-with-brd4-to-promote-tat-and-p-tefb-association
#5
Huachao Huang, Shuai Liu, Maxime Jean, Sydney Simpson, He Huang, Mark Merkley, Tsuyoshi Hayashi, Weili Kong, Irene Rodríguez-Sánchez, Xiaofeng Zhang, Hailemichael O Yosief, Hongyu Miao, Jianwen Que, James J Kobie, James Bradner, Netty G Santoso, Wei Zhang, Jian Zhu
While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28557951/are-scores-from-nbme-subject-examinations-valid-measures-of-knowledge-acquired-during-clinical-clerkships
#6
Michael S Ryan, Steven Bishop, Joel Browning, Rahul J Anand, Elizabeth Waterhouse, Fidelma Rigby, Cheryl S Al-Mateen, Clifton Lee, Melissa Bradner, Jorie M Colbert-Getz
PURPOSE: The National Board of Medical Examiners' Clinical Science Subject Examinations are a component used by most U.S. medical schools to determine clerkship grades. The purpose of this study was to examine the validity of this practice. METHOD: This was a retrospective cohort study of medical students at the Virginia Commonwealth University School of Medicine who completed clerkships in 2012 through 2014. Linear regression was used to determine how well United States Medical Licensing Examination Step 1 scores predicted Subject Examination scores in seven clerkships...
June 2017: Academic Medicine: Journal of the Association of American Medical Colleges
https://www.readbyqxmd.com/read/28535045/bet-bromodomain-inhibitors-with-one-step-synthesis-discovered-from-virtual-screen
#7
Alex M Ayoub, Laura M L Hawk, Ryan J Herzig, Jiewei Jiang, Andrea J Wisniewski, Clifford T Gee, Peiliang Zhao, Jin-Yi Zhu, Norbert Berndt, Nana K Offei-Addo, Thomas G Scott, Jun Qi, James E Bradner, Timothy R Ward, Ernst Schönbrunn, Gunda I Georg, William C K Pomerantz
Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity...
June 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28490664/inhibiting-the-oncogenic-translation-program-is-an-effective-therapeutic-strategy-in-multiple-myeloma
#8
Salomon Manier, Daisy Huynh, Yu J Shen, Jia Zhou, Timur Yusufzai, Karma Z Salem, Richard Y Ebright, Jiantao Shi, Jihye Park, Siobhan V Glavey, William G Devine, Chia-Jen Liu, Xavier Leleu, Bruno Quesnel, Catherine Roche-Lestienne, John K Snyder, Lauren E Brown, Nathanael Gray, James Bradner, Luke Whitesell, John A Porco, Irene M Ghobrial
Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate...
May 10, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28332503/a-chemical-probe-toolbox-for-dissecting-the-cancer-epigenome
#9
Jake Shortt, Christopher J Ott, Ricky W Johnstone, James E Bradner
No abstract text is available yet for this article.
March 23, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28249162/bet-bromodomain-inhibitors-engage-the-host-immune-system-and-regulate-expression-of-the-immune-checkpoint-ligand-pd-l1
#10
Simon J Hogg, Stephin J Vervoort, Sumit Deswal, Christopher J Ott, Jason Li, Leonie A Cluse, Paul A Beavis, Phillip K Darcy, Benjamin P Martin, Andrew Spencer, Anna K Traunbauer, Irina Sadovnik, Karin Bauer, Peter Valent, James E Bradner, Johannes Zuber, Jake Shortt, Ricky W Johnstone
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28228643/a-chemical-probe-toolbox-for-dissecting-the-cancer-epigenome
#11
REVIEW
Jake Shortt, Christopher J Ott, Ricky W Johnstone, James E Bradner
Cancer cell hallmarks are underpinned by transcriptional programmes operating in the context of a dynamic and complicit epigenomic environment. Somatic alterations of chromatin modifiers are among the most prevalent cancer perturbations. There is a pressing need for targeted chemical probes to dissect these complex, interconnected gene regulatory circuits. Validated chemical probes empower mechanistic research while providing the pharmacological proof of concept that is required to translate drug-like derivatives into therapy for cancer patients...
February 23, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28169291/hotspots-of-aberrant-enhancer-activity-punctuate-the-colorectal-cancer-epigenome
#12
Andrea J Cohen, Alina Saiakhova, Olivia Corradin, Jennifer M Luppino, Katreya Lovrenert, Cynthia F Bartels, James J Morrow, Stephen C Mack, Gursimran Dhillon, Lydia Beard, Lois Myeroff, Matthew F Kalady, Joseph Willis, James E Bradner, Ruth A Keri, Nathan A Berger, Shondra M Pruett-Miller, Sanford D Markowitz, Peter C Scacheri
In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin...
February 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/27862999/assessment-of-bromodomain-target-engagement-by-a-series-of-bi2536-analogues-with-miniaturized-bet-bret
#13
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
#14
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
#15
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
#16
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...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27590350/multi-focal-control-of-mitochondrial-gene-expression-by-oncogenic-myc-provides-potential-therapeutic-targets-in-cancer
#17
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...
November 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27535106/targeting-chromatin-regulators-inhibits-leukemogenic-gene-expression-in-npm1-mutant-leukemia
#18
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
#19
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
#20
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
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