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https://www.readbyqxmd.com/read/28448849/regulation-of-the-human-papillomavirus-type-16-late-promoter-by-transcriptional-elongation
#1
William K Songock, Matthew L Scott, Jason M Bodily
Transcripts from the late promoter of human papillomavirus type 16 (HPV16) are upregulated upon host cell differentiation. Differentiation-dependent transcript regulation is thought to sequester viral antigens in the uppermost epithelial layers, facilitating immune evasion. The mechanisms regulating late promoter upregulation during differentiation are poorly characterized. We show that the late promoter is upregulated at the transcriptional level and that the viral enhancer stimulates promoter activity. Using kinase inhibition and chromatin immunoprecipitation analysis, we show evidence for differentiation-dependent enhancement of transcript elongation...
April 24, 2017: Virology
https://www.readbyqxmd.com/read/28446439/pax3-foxo1-establishes-myogenic-super-enhancers-and-confers-bet-bromodomain-vulnerability
#2
Berkley E Gryder, Marielle E Yohe, Hsien-Chao Chou, Xiaohu Zhang, Joana Marques, Marco Wachtel, Beat Schaefer, Nirmalya Sen, Young K Song, Alberto Gualtieri, Silvia Pomella, Rossella Rota, Abigail Cleveland, Xinyu Wen, Sivasish Sindiri, Jun S Wei, Frederic G Barr, Sudipto Das, Thorkell Andresson, Rajarshi Guha, Madhu Lal-Nag, Marc Ferrer, Jack F Shern, Keji Zhao, Craig J Thomas, Javed Khan
Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1 (P3F). The mechanisms by which P3F dysregulates chromatin are unknown. We find P3F reprograms the cis-regulatory landscape by inducing (de novo) super enhancers (SEs). P3F uses SEs to setup auto-regulatory loops in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors...
April 26, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28439316/epigenetic-assays-for-chemical-biology-and-drug-discovery
#3
REVIEW
Sheraz Gul
The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28434841/transcriptional-dependencies-in-diffuse-intrinsic-pontine-glioma
#4
Surya Nagaraja, Nicholas A Vitanza, Pamelyn J Woo, Kathryn R Taylor, Fang Liu, Lei Zhang, Meng Li, Wei Meng, Anitha Ponnuswami, Wenchao Sun, Jie Ma, Esther Hulleman, Tomek Swigut, Joanna Wysocka, Yujie Tang, Michelle Monje
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade...
April 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28426098/targeting-chromatin-defects-in-selected-solid-tumors-based-on-oncogene-addiction-synthetic-lethality-and-epigenetic-antagonism
#5
D Morel, G Almouzni, J-C Soria, S Postel-Vinay
Background: Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors...
February 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28423651/succinate-dehydrogenase-b-deficient-cancer-cells-are-highly-sensitive-to-bromodomain-and-extra-terminal-inhibitors
#6
Satoshi Kitazawa, Shunsuke Ebara, Ayumi Ando, Yuji Baba, Yoshinori Satomi, Tomoyoshi Soga, Takahito Hara
Mutations in succinate dehydrogenase B (SDHB) gene are frequently observed in several tumors and associated with poor prognosis in these tumors. Therefore, drugs effective for SDHB-deficient tumors could fulfill an unmet medical need. In addition, such drugs would have an advantage in that selection of patients with SDHB-mutant cancer could increase the probability of success in clinical trials. Currently, however, the characteristics of SDHB-deficient cancers are not completely understood. Here, we established SDHB knockout cancer cell lines from human colon cancer HCT116 cells using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 knockout system, and clarified its metabolic characteristics...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420416/emerging-therapies-for-acute-myeloid-leukemia
#7
REVIEW
Caner Saygin, Hetty E Carraway
Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors...
April 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28418907/bh3-mimetics-and-bet-inhibitors-elicit-enhanced-lethality-in-malignant-glioma
#8
Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin
Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL and c-myc inhibition accomplished by bromodomain protein inhibitors. Established, patient-derived xenograft and stem cell-like glioma cells were treated with the novel bromodomain protein inhibitors, JQ1 and OTX015, along with BH3-mimetics, ABT263 or Obatoclax. Synergy was assessed by calculation of CI values. Small interfering RNAs (siRNAs) were used for gene silencing and mechanistic studies...
March 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418626/degradation-of-the-baf-complex-factor-brd9-by-heterobifunctional-ligands
#9
David Remillard, Dennis L Buckley, Joshiawa Paulk, Gerard L Brien, Matthew Sonnett, Hyuk-Soo Seo, Shiva Dastierdi, Martin Wühr, Sirano Dhe-Paganon, Scott A Armstrong, James E Bradner
The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex...
April 18, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28416490/preclinical-characterization-of-bet-family-bromodomain-inhibitor-abbv-075-suggests-combination-therapeutic-strategies
#10
Mai H Bui, Xiaoyu Lin, Daniel H Albert, Leiming Li, Lloyd T Lam, Emily J Faivre, Scott Warder, Xiaoli Huang, Denise Wilcox, Cherrie K Donawho, George S Sheppard, Le Wang, Steve Fidanze, John K Pratt, Dachun Liu, Lisa Hasvold, Tamar Uziel, Xin Lu, Fred Kohlhapp, Guowei Fang, Steven W Elmore, Saul H Rosenberg, Keith F McDaniel, Warren M Kati, Yu Shen
ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models representing a variety of hematological malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) cells...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28415755/mitochondrial-matrix-chaperone-and-c-myc-inhibition-causes-enhanced-lethality-in-glioblastoma
#11
Chiaki Tsuge Ishida, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Dario C Altieri, Georg Karpel-Massler, Markus David Siegelin
Malignant gliomas display high levels of the transcription factor c-myc and organize a tumor specific chaperone network within mitochondria. Here, we show that c-myc along with mitochondrial chaperone inhibition displays massive tumor cell death. Inhibition of mitochondrial matrix chaperones and c-myc was established by utilizing genetic as well as pharmacological approaches. Bromodomain and extraterminal (BET) family protein inhibitors, JQ1 and OTX015, were used for c-myc inhibition. Gamitrinib was applied to interfere with mitochondrial matrix chaperones...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415703/bromodomain-protein-4-is-a-novel-predictor-of-survival-for-gastric-carcinoma
#12
Yixin Zhu, Weijin Yang, Guangnian Ji, Nan Lin, Weihang Wu, Ping Xiong, Chenxin Zheng, Lei Yan, Peng Wan, Yu Wang
Expression of bromodomain protein 4 (BRD4) has been reported to predict a worse prognosis in solid tumors. However, its expression profile and prognostic value in gastric carcinoma (GC) remains unknown. Here we investigated BRD4 expression in GC and explored its association with patient survival. Tissue samples were obtained from 95 GC patients who underwent surgical resection to remove the primary tumor from January 2009 to December 2010. Immunohistochemistry was used to detect the expression of BRD4 in GC tissues and adjacent normal tissues...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28410781/virtual-screen-to-nmr-vs2nmr-discovery-of-fragment-hits-for-the-cbp-bromodomain
#13
Dimitrios Spiliotopoulos, Jian Zhu, Eike-Christian Wamhoff, Nicholas Deerain, Jean-Rémy Marchand, Jonas Aretz, Christoph Rademacher, Amedeo Caflisch
Overexpression of the CREB-binding protein (CBP), a bromodomain-containing transcription coactivator involved in a variety of cellular processes, has been observed in several types of cancer with a correlation to aggressiveness. We have screened a library of nearly 1500 fragments by high-throughput docking into the CBP bromodomain followed by binding energy evaluation using a force field with electrostatic solvation. Twenty of the 39 fragments selected by virtual screening are positive in one or more ligand-observed nuclear magnetic resonance (NMR) experiments...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28408401/synergistic-immunostimulatory-effects-and-therapeutic-benefit-of-combined-histone-deacetylase-and-bromodomain-inhibition-in-non-small-cell-lung-cancer
#14
Dennis Adeegbe, Yan Liu, Patrick H Lizotte, Yusuke Kamihara, Amir R Aref, Christina Almonte, Ruben Dries, Yuyang Li, Shengwu Liu, Xiaoen Wang, Tiquella Warner-Hatten, Jessica Castrillon, Guo-Cheng Yuan, Neermala Poudel-Neupane, Haikuo Zhang, Jennifer L Guerriero, Shiwei Han, Mark M Awad, David A Barbie, Jerome Ritz, Simon S Jones, Peter S Hammerman, James E Bradner, Steven N Quayle, Kwok-Kin Wong
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response...
April 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28402630/benzo-isoquinoline-diones-as-potent-and-selective-inhibitors-of-brpf2-and-taf1-taf1l-bromodomains
#15
Léa Bouché, Clara D Christ, Stephan Siegel, Amaury E Fernández-Montalván, Simon J Holton, Oleg Fedorov, Antonius Ter Laak, Tatsuo Sugawara, Detlef Stöckigt, Cynthia Tallant, James M Bennett, Octovia P Monteiro, Laura Díaz-Sáez, Paulina Siejka, Julia Meier, Vera Puetter, Joerg Weiske, Susanne Müller, Kilian Veit Marcus Huber, Ingo V Hartung, Bernard Haendler
Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzo-isoquinoline-dione series was identified by high-througput screening and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs...
April 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28391274/inhibition-of-brd4-suppresses-cell-proliferation-and-induces-apoptosis-in-renal-cell-carcinoma
#16
Xinchao Wu, Dong Liu, Xuemei Gao, Fei Xie, Dan Tao, Xingyuan Xiao, Liang Wang, Guosong Jiang, Fuqing Zeng
BACKGROUND/AIMS: Renal cell carcinoma (RCC) remains an intractable genitourinary malignancy. Resistance to chemotherapy or targeted therapies in RCC is presumably due to the complicated underlying molecular mechanisms and insufficient understanding. The aim of this research was to assess the expression and role of bromodomain-4 protein (BRD4) in RCC and evaluate the effects of BRD4 inhibitor JQ1 for RCC treatment. METHODS: BRD4 expressionlevels were assessed by qRT-PCR and western blot in RCC tissues and cells...
April 7, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28388437/the-bet-protein-brd2-cooperates-with-ctcf-to-enforce-transcriptional-and-architectural-boundaries
#17
Sarah C Hsu, Thomas G Gilgenast, Caroline R Bartman, Christopher R Edwards, Aaron J Stonestrom, Peng Huang, Daniel J Emerson, Perry Evans, Michael T Werner, Cheryl A Keller, Belinda Giardine, Ross C Hardison, Arjun Raj, Jennifer E Phillips-Cremins, Gerd A Blobel
Bromodomain and extraterminal motif (BET) proteins are pharmacologic targets for the treatment of diverse diseases, yet the roles of individual BET family members remain unclear. We find that BRD2, but not BRD4, co-localizes with the architectural/insulator protein CCCTC-binding factor (CTCF) genome-wide. CTCF recruits BRD2 to co-bound sites whereas BRD2 is dispensable for CTCF occupancy. Disruption of a CTCF/BRD2-occupied element positioned between two unrelated genes enables regulatory influence to spread from one gene to another, suggesting that CTCF and BRD2 form a transcriptional boundary...
April 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28378579/a-click-chemistry-platform-for-the-rapid-synthesis-of-bispecific-molecules-for-inducing-protein-degradation
#18
Ryan P Wurz, Ken Dellamaggiore, Hannah Dou, Noelle Javier, Mei-Chu Lo, John D McCarter, Dane Mohl, Christine Sastri, J Russell Lipford, Victor J Cee
Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs...
April 5, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28375629/structure-based-design-of-highly-selective-inhibitors-of-the-creb-binding-protein-bromodomain
#19
Rajiah Aldrin Denny, Andrew C Flick, Jotham Wadsworth Coe, Jonathan Langille, Arindrajit Basak, Shenping Liu, Ingrid A Stock, Parag Sahasrabudhe, Paul D Bonin, Duncan Alexander Hay, Paul E Brennan, Mathew T Pletcher, Lyn H Jones, Eugene L Piatnitski Chekler
Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB Binding Protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization, that paid particular attention to physiochemical properties, delivered chemical probes with desirable potency, selectivity and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein)...
April 4, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28373363/re-engineering-the-pancreas-tumor-microenvironment-a-regenerative-program-hacked
#20
EDITORIAL
Gerard I Evan, Nasun Hah, Trevor D Littlewood, Nicole M Sodir, Tania Campos, Michael Downes, Ronald M Evans
The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks...
April 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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