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Bromodomain inhibitors

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https://www.readbyqxmd.com/read/28336808/potent-dual-bet-bromodomain-kinase-inhibitors-as-value-added-multi-targeted-chemical-probes-and-cancer-therapeutics
#1
Stuart W Ember, Que T Lambert, Norbert Berndt, Steven Gunawan, Muhammad Ayaz, Marilena Tauro, Jin-Yi Zhu, Paula J Cranfill, Patricia Greninger, Conor C Lynch, Cyril H Benes, Harshani R Lawrence, Gary W Reuther, Nicholas J Lawrence, Ernst Schonbrunn
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348 we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from myeloproliferative neoplasm (MPN) patients...
March 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28300771/inhibitors-of-brd4-protein-from-a-marine-derived-fungus-alternaria-sp-nh-f6
#2
Hui Ding, Dashan Zhang, Biao Zhou, Zhongjun Ma
Bromodomains (BRD) are readers of the epigenetic code that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Recently, bromodomain-containing proteins such as BRD4 have been demonstrated to be druggable through the discovery of potent inhibitors. These protein-protein interaction inhibitors have the potential to modulate multiple diseases by their profound anti-inflammatory and antiproliferative effects. In order to explore new BRD4 inhibitors as well as lead compounds for the development of new drugs, the secondary metabolites of Alternaria sp...
March 16, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28292938/combinatorial-screening-of-pancreatic-adenocarcinoma-reveals-sensitivity-to-drug-combinations-including-bromodomain-inhibitor-plus-neddylation-inhibitor
#3
Casey G Langdon, James T Platt, Robert E Means, Pinar Iyidogan, Ramanaiah Mamillapalli, Michael Klein, Matthew A Held, Jong Woo Lee, Ja Seok Koo, Christos Hatzis, Howard S Hochster, David F Stern
Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28286180/dysregulation-of-bet-proteins-in-levodopa-induced-dyskinesia
#4
David A Figge, David G Standaert
Levodopa (L-DOPA) remains the most effective pharmacological treatment for Parkinson Disease (PD) but its use is limited by the development of debilitating drug-related side effects, particularly L-DOPA induced dyskinesia (LID). LID is a consequence of long-term L-DOPA use, and in model systems is characterized by a "priming effect", whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent dopaminergic stimulation. Preliminary studies into the mechanisms underlying this cellular memory have indicated an important role for epigenetic change but many of the downstream mechanisms remain unknown...
March 9, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28283057/super-enhancer-mediated-rna-processing-revealed-by-integrative-microrna-network-analysis
#5
Hiroshi I Suzuki, Richard A Young, Phillip A Sharp
Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function...
March 9, 2017: Cell
https://www.readbyqxmd.com/read/28279785/epigenetic-interventions-for-epileptogenesis-a-new-frontier-for-curing-epilepsy
#6
REVIEW
Iyan Younus, Doodipala Samba Reddy
This article highlights the emerging therapeutic potential of specific epigenetic modulators as promising antiepileptogenic or disease-modifying agents for curing epilepsy. Currently, there is an unmet need for antiepileptogenic agents that truly prevent the development of epilepsy in people at risk. There is strong evidence that epigenetic signaling, which exerts high fidelity regulation of gene expression, plays a crucial role in the pathophysiology of epileptogenesis and chronic epilepsy. These modifications are not hard-wired into the genome and are constantly reprogrammed by environmental influences...
March 6, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28275007/gene-expression-profiling-of-patient-derived-pancreatic-cancer-xenografts-predicts-sensitivity-to-the-bet-bromodomain-inhibitor-jq1-implications-for-individualized-medicine-efforts
#7
Benjamin Bian, Martin Bigonnet, Odile Gayet, Celine Loncle, Aurélie Maignan, Marine Gilabert, Vincent Moutardier, Stephane Garcia, Olivier Turrini, Jean-Robert Delpero, Marc Giovannini, Philippe Grandval, Mohamed Gasmi, Mehdi Ouaissi, Veronique Secq, Flora Poizat, Rémy Nicolle, Yuna Blum, Laetitia Marisa, Marion Rubis, Jean-Luc Raoul, James E Bradner, Jun Qi, Gwen Lomberk, Raul Urrutia, Andres Saul, Nelson Dusetti, Juan Iovanna
c-MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup...
March 8, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28270499/pd-l1-is-a-therapeutic-target-of-the-bromodomain-inhibitor-jq1-and-combined-with-hla-class-i-a-promising-prognostic-biomarker-in-neuroblastoma
#8
Ombretta Melaiu, Marco Mina, Marco Chierici, Renata Boldrini, Giuseppe Jurman, Paolo Romania, Valerio D'Alicandro, Maria Chiara Benedetti, Aurora Castellano, Tao Liu, Cesare Furlanello, Franco Locatelli, Doriana Fruci
PURPOSE: This study sought to evaluate expression of PD-L1 and HLA class I on neuroblastoma cells and PD-1 and LAG3 on tumor-infiltrating lymphocytes to better define patient risk-stratification and understand whether this tumor may benefit from therapies targeting immune-checkpoint molecules. EXPERIMENTAL DESIGN: In situ immunohistochemical staining for PD-L1, HLA class I, PD-1 and LAG3 was assessed in 77 neuroblastoma specimens, previously characterized for tumor-infiltrating T cell-density, and correlated with clinical outcome...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28268136/methylpyrrole-inhibitors-of-bet-bromodomains
#9
Lisa A Hasvold, George S Sheppard, Le Wang, Steven D Fidanze, Dachun Liu, John K Pratt, Robert A Mantei, Carol K Wada, Robbert Hubbard, Yu Shen, Xiaoyu Lin, Xiaoli Huang, Scott E Warder, Denise Wilcox, Leiming Li, F Greg Buchanan, Lauren Smithee, Daniel H Albert, Terrance J Magoc, Chang H Park, Andrew M Petros, Sanjay C Panchal, Chaohong Sun, Peter Kovar, Nirupama B Soni, Steven W Elmore, Warren M Kati, Keith F McDaniel
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
February 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28265070/bet-n-terminal-bromodomain-inhibition-selectively-blocks-th17-cell-differentiation-and-ameliorates-colitis-in-mice
#10
Kalung Cheung, Geming Lu, Rajal Sharma, Adam Vincek, Ruihua Zhang, Alexander N Plotnikov, Fan Zhang, Qiang Zhang, Ying Ju, Yuan Hu, Li Zhao, Xinye Han, Jamel Meslamani, Feihong Xu, Anbalagan Jaganathan, Tong Shen, Hongfa Zhu, Elena Rusinova, Lei Zeng, Jiachi Zhou, Jianjun Yang, Liang Peng, Michael Ohlmeyer, Martin J Walsh, David Y Zhang, Huabao Xiong, Ming-Ming Zhou
T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4(+) T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential...
March 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28263307/therapeutic-targeting-of-polycomb-and-bet-bromodomain-proteins-in-diffuse-intrinsic-pontine-gliomas
#11
Andrea Piunti, Rintaro Hashizume, Marc A Morgan, Elizabeth T Bartom, Craig M Horbinski, Stacy A Marshall, Emily J Rendleman, Quanhong Ma, Yoh-Hei Takahashi, Ashley R Woodfin, Alexander V Misharin, Nebiyu A Abshiru, Rishi R Lulla, Amanda M Saratsis, Neil L Kelleher, C David James, Ali Shilatifard
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis...
February 27, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28261211/targeting-the-monocyte-macrophage-lineage-in-solid-organ-transplantation
#12
REVIEW
Thierry P P van den Bosch, Nynke M Kannegieter, Dennis A Hesselink, Carla C Baan, Ajda T Rowshani
There is an unmet clinical need for immunotherapeutic strategies that specifically target the active immune cells participating in the process of rejection after solid organ transplantation. The monocyte-macrophage cell lineage is increasingly recognized as a major player in acute and chronic allograft immunopathology. The dominant presence of cells of this lineage in rejecting allograft tissue is associated with worse graft function and survival. Monocytes and macrophages contribute to alloimmunity via diverse pathways: antigen processing and presentation, costimulation, pro-inflammatory cytokine production, and tissue repair...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28254412/bromodomain-inhibitors-jq1-and-i-bet-762-as-potential-therapies-for-pancreatic-cancer
#13
Ana S Leal, Charlotte R Williams, Darlene B Royce, Patricia A Pioli, Michael B Sporn, Karen T Liby
Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of selective, small molecule inhibitors that target BET (bromodomain and extra terminal) proteins. By impairing their ability to bind to acetylated lysines on histones, bromodomain inhibitors interfere with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. In this study, JQ1 and I-BET 762 decreased c-Myc and p-Erk 1/2 protein levels and inhibited proliferation in pancreatic cancer cells...
February 27, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28249162/bet-bromodomain-inhibitors-engage-the-host-immune-system-and-regulate-expression-of-the-immune-checkpoint-ligand-pd-l1
#14
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/28248992/altered-regulation-and-expression-of-genes-by-bet-family-of-proteins-in-copd-patients
#15
Rajneesh Malhotra, Nisha Kurian, Xiao-Hong Zhou, Fanyi Jiang, Susan Monkley, Amy DeMicco, Ib G Clausen, Göran Delgren, Goran Edenro, Miika J Ahdesmäki, Maryam Clausen, Lisa Öberg, Elisabeth Israelsson, Graham Belfield, Outi Vaarala
BACKGROUND: BET proteins (BRD2, BRD3, BRDT and BRD4) belong to the family of bromodomain containing proteins, which form a class of transcriptional co-regulators. BET proteins bind to acetylated lysine residues in the histones of nucleosomal chromatin and function either as co-activators or co-repressors of gene expression. An imbalance between HAT and HDAC activities resulting in hyperacetylation of histones has been identified in COPD. We hypothesized that pan-BET inhibitor (JQ1) treatment of BET protein interactions with hyperacetylated sites in the chromatin will regulate excessive activation of pro-inflammatory genes in key inflammatory drivers of alveolar macrophages (AM) in COPD...
2017: PloS One
https://www.readbyqxmd.com/read/28241141/enl-links-histone-acetylation-to-oncogenic-gene-expression-in-acute-myeloid-leukaemia
#16
Liling Wan, Hong Wen, Yuanyuan Li, Jie Lyu, Yuanxin Xi, Takayuki Hoshii, Julia K Joseph, Xiaolu Wang, Yong-Hwee E Loh, Michael A Erb, Amanda L Souza, James E Bradner, Li Shen, Wei Li, Haitao Li, C David Allis, Scott A Armstrong, Xiaobing Shi
Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown...
March 9, 2017: Nature
https://www.readbyqxmd.com/read/28215221/targeting-chromatin-remodeling-in-inflammation-and-fibrosis
#17
J Yang, B Tian, A R Brasier
Mucosal surfaces of the human body are lined by a contiguous epithelial cell surface that forms a barrier to aerosolized pathogens. Specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host responses by triggering activation of the nuclear factor κB (NFκB)/RelA transcription factor and formation of a complex with the positive transcription elongation factor (P-TEFb)/cyclin-dependent kinase (CDK)9 and Bromodomain-containing protein 4 (BRD4) epigenetic reader...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28213432/targeting-cancer-cells-with-bet-bromodomain-inhibitors
#18
Yali Xu, Christopher R Vakoc
Cancer cells are often hypersensitive to the targeting of transcriptional regulators, which may reflect the deregulated gene expression programs that underlie malignant transformation. One of the most prominent transcriptional vulnerabilities in human cancer to emerge in recent years is the bromodomain and extraterminal (BET) family of proteins, which are coactivators that link acetylated transcription factors and histones to the activation of RNA polymerase II. Despite unclear mechanisms underlying the gene specificity of BET protein function, small molecules targeting these regulators preferentially suppress the transcription of cancer-promoting genes...
February 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28209615/targeted-degradation-of-bet-proteins-in-triple-negative-breast-cancer
#19
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer L Meagher, Jeanne Stuckey, Daniel F Hayes, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28207202/the-polar-warhead-of-a-trim24-bromodomain-inhibitor-rearranges-a-water-mediated-interaction-network
#20
Jiuyang Liu, Fudong Li, Hongyu Bao, Yiyang Jiang, Shuya Zhang, Rongsheng Ma, Jia Gao, Jihui Wu, Ke Ruan
Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors...
February 16, 2017: FEBS Journal
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