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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/28322577/bet-proteins-are-a-key-component-of-immunoglobulin-gene-expression
#2
Jung Min Shim, Jin S Lee, Kirsty E Russell, Coen H Wiegman, Peter J Barnes, David Fear, Ian M Adcock, Andrew L Durham
AIM: BET proteins have been shown to regulate gene expression including inflammatory genes. METHODS: In order to investigate the role of the BET proteins in immunoglobulin production we treated the human B-cell line CLNH11.4 and primary human B cells and ozone-exposed mice with BET inhibitors (JQ1 or IBET151). RESULTS: Both proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription...
March 21, 2017: Epigenomics
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/28275007/gene-expression-profiling-of-patient-derived-pancreatic-cancer-xenografts-predicts-sensitivity-to-the-bet-bromodomain-inhibitor-jq1-implications-for-individualized-medicine-efforts
#6
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
#7
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/28265070/bet-n-terminal-bromodomain-inhibition-selectively-blocks-th17-cell-differentiation-and-ameliorates-colitis-in-mice
#8
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/28254412/bromodomain-inhibitors-jq1-and-i-bet-762-as-potential-therapies-for-pancreatic-cancer
#9
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
#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/28248992/altered-regulation-and-expression-of-genes-by-bet-family-of-proteins-in-copd-patients
#11
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/28143717/the-bet-bromodomain-inhibitor-jq1-radiosensitizes-non-small-cell-lung-cancer-cells-by-upregulating-p21
#12
Jian Wang, Ye Wang, Hong Mei, Zhongyuan Yin, Yuanyuan Geng, Tao Zhang, Gang Wu, Zhenyu Lin
Radiotherapy is an important treatment modality in the management of locally advanced non-small cell lung cancer (NSCLC). However, radioresistance markedly impairs its efficacy in clinic. Bromodomain and extra-terminal (BET) bromodomain inhibitors have demonstrated dramatic antitumor activity in several preclinical human cancer models. In this study, we investigated for the first time the effect of JQ1, a novel BET bromodomain inhibitor, on tumor cell radiosensitivity of NSCLC in vitro and in vivo. Our results demonstrated that JQ1 significantly enhanced the effect of irradiation in NSCLC cell lines through a c-myc-independent mechanism...
April 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28134933/inhibition-of-the-integrin-fak-signaling-axis-and-c-myc-synergistically-disrupts-ovarian-cancer-malignancy
#13
B Xu, J Lefringhouse, Z Liu, D West, L A Baldwin, C Ou, L Chen, D Napier, L Chaiswing, L D Brewer, D St Clair, O Thibault, J R van Nagell, B P Zhou, R Drapkin, J-A Huang, M L Lu, F R Ueland, X H Yang
Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor...
January 30, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28119527/runx3-is-oncogenic-in-natural-killer-t-cell-lymphoma-and-is-transcriptionally-regulated-by-myc
#14
V Selvarajan, M Osato, G S S Nah, J Yan, C Tae-Hoon, Dc-C Voon, Y Ito, M F Ham, M Salto-Tellez, N Shimizu, S-N Choo, S Fan, W-J Chng, S-B Ng
RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppresser in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal NK/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region...
January 25, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28118076/targeting-ampk-ulk1-mediated-autophagy-for-combating-bet-inhibitor-resistance-in-acute-myeloid-leukemia-stem-cells
#15
Ji Eun Jang, Ju-In Eom, Hoi-Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. We evaluated the levels of apoptosis and macroautophagy/autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+) CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations...
January 24, 2017: Autophagy
https://www.readbyqxmd.com/read/28107481/bet-inhibitors-disrupt-rad21-dependent-conformational-control-of-kshv-latency
#16
Horng-Shen Chen, Alessandra De Leo, Zhuo Wang, Andrew Kerekovic, Robert Hills, Paul M Lieberman
Kaposi's Sarcoma-associated Herpesvirus (KSHV) establishes stable latent infection in B-lymphocytes and pleural effusion lymphomas (PELs). During latency, the viral genome persists as an epigenetically constrained episome with restricted gene expression programs. To identify epigenetic regulators of KSHV latency, we screened a focused small molecule library containing known inhibitors of epigenetic factors. We identified JQ1, a Bromodomain and Extended Terminal (BET) protein inhibitor, as a potent activator of KSHV lytic reactivation from B-cells carrying episomal KSHV...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28103888/photoreceptor-protection-via-blockade-of-bet-epigenetic-readers-in-a-murine-model-of-inherited-retinal-degeneration
#17
Lei Zhao, Jun Li, Yingmei Fu, Mengxue Zhang, Bowen Wang, Jonathan Ouellette, Pawan K Shahi, Bikash R Pattnaik, Jyoti J Watters, Wai T Wong, Lian-Wang Guo
BACKGROUND: The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, and BET4) "read" (bind) histone acetylation marks via two distinct bromodomains (Brom1 and Brom2) facilitating transcriptional activation. These epigenetic "readers" play crucial roles in pathogenic processes such as inflammation. The role of BETs in influencing the degenerative process in the retina is however unknown. METHODS: We employed the rd10 mouse model (Pde6b (rd10) mutation) of retinitis pigmentosa (RP) to examine the involvement of BET proteins in retinal neurodegeneration...
January 19, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28100400/replication-study-bet-bromodomain-inhibition-as-a-therapeutic-strategy-to-target-c-myc
#18
Fraser Aird, Irawati Kandela, Christine Mantis
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al...
January 19, 2017: ELife
https://www.readbyqxmd.com/read/28074072/targeting-bet-proteins-improves-the-therapeutic-efficacy-of-bcl-2-inhibition-in-t-cell-acute-lymphoblastic-leukemia
#19
S Peirs, V Frismantas, F Matthijssens, W Van Loocke, T Pieters, N Vandamme, B Lintermans, M P Dobay, G Berx, B Poppe, S Goossens, B C Bornhauser, J-P Bourquin, P Van Vlierberghe
Inhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28069948/genomic-targeting-of-epigenetic-probes-using-a-chemically-tailored-cas9-system
#20
Glen P Liszczak, Zachary Z Brown, Samuel H Kim, Rob C Oslund, Yael David, Tom W Muir
Recent advances in the field of programmable DNA-binding proteins have led to the development of facile methods for genomic localization of genetically encodable entities. Despite the extensive utility of these tools, locus-specific delivery of synthetic molecules remains limited by a lack of adequate technologies. Here we combine the flexibility of chemical synthesis with the specificity of a programmable DNA-binding protein by using protein trans-splicing to ligate synthetic elements to a nuclease-deficient Cas9 (dCas9) in vitro and subsequently deliver the dCas9 cargo to live cells...
January 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
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