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Bromodomain

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https://www.readbyqxmd.com/read/28642448/combined-brd4-and-cdk9-inhibition-as-a-new-therapeutic-approach-in-malignant-rhabdoid-tumors
#1
Natalia Moreno, Till Holsten, Julius Mertins, Annabelle Zhogbi, Pascal Johann, Marcel Kool, Michael Meisterernst, Kornelius Kerl
Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds...
June 21, 2017: Oncotarget
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
#2
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/28636389/tumor-microenvironment-responsive-multistaged-nanoplatform-for-systemic-rnai-and-cancer-therapy
#3
Xiaoding Xu, Phei Er Saw, Wei Tao, Yujing Li, Xiaoyuan Ji, Mikyung Yu, Morteza Mahmoudi, Jonathan Rasmussen, Dana Ayyash, Yuxiao Zhou, Omid C Farokhzad, Jinjun Shi
While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core...
June 21, 2017: Nano Letters
https://www.readbyqxmd.com/read/28636361/a-machine-learning-assisted-approach-for-discovering-novel-inhibitors-targeting-bromodomain-containing-protein-4
#4
Jing Xing, Wenchao Lu, Rongfeng Liu, Yulan Wang, Yiqian Xie, Hao Zhang, Zhe Shi, Hao Jiang, Yu-Chih Liu, Kaixian Chen, Hualiang Jiang, Cheng Luo, Mingyue Zheng
Bromodomain-containing protein 4 (BRD4) is implicated in the pathogenesis of a number of different cancers, inflammatory diseases and heart failure. Much effort has been dedicated toward discovering novel scaffold BRD4 inhibitors (BRD4is) with different selectivity profiles and potential anti-resistance properties. Structure-based drug design (SBDD) and virtual screening (VS) are the most frequently used approaches. Here, we demonstrate a novel, structure-based VS approach that uses machine-learning algorithms trained on the priori structure and activity knowledge to predict the likelihood that a compound is a BRD4i based on its binding pattern with BRD4...
June 21, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28630323/role-of-the-cbp-catalytic-core-in-intramolecular-sumoylation-and-control-of-histone-h3-acetylation
#5
Sangho Park, Robyn L Stanfield, Maria A Martinez-Yamout, H Jane Dyson, Ian A Wilson, Peter E Wright
The histone acetyl transferases CREB-binding protein (CBP) and its paralog p300 play a critical role in numerous cellular processes. Dysregulation of their catalytic activity is associated with several human diseases. Previous work has elucidated the regulatory mechanisms of p300 acetyltransferase activity, but it is not known whether CBP activity is controlled similarly. Here, we present the crystal structure of the CBP catalytic core encompassing the bromodomain (BRD), CH2 (comprising PHD and RING), HAT, and ZZ domains at 2...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28626565/site-specific-azide-acetyllysine-photochemistry-on-epigenetic-readers-for-interactome-profiling
#6
Babu Sudhamalla, Debasis Dey, Megan Breski, Tiffany Nguyen, Kabirul Islam
Chemical modifications on DNA, RNA and histones are recognized by an array of 'reader' modules to regulate transcriptional programming and cell fate. However, identification of reader-specific interacting partners in a dynamic cellular environment remains a significant challenge. Herein, we report a chemoproteomic approach termed 'interaction-based protein profiling' (IBPP) to characterize novel interacting partners of potentially any reader protein. IBPP harnesses a photosensitive amino acid introduced into the hydrophobic pocket of a reader module to crosslink and enrich transient interacting partners that are inaccessible to traditional methods...
June 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28624801/bromodomain-inhibition-shows-antitumoral-activity-in-mice-and-human-luminal-breast-cancer
#7
Montserrat Pérez-Salvia, Laia Simó-Riudalbas, Pere Llinàs-Arias, Laura Roa, Fernando Setien, Marta Soler, Manuel Castro de Moura, James E Bradner, Eva Gonzalez-Suarez, Catia Moutinho, Manel Esteller
BET bromodomain inhibitors, which have an antitumoral effect against various solid cancer tumor types, have not been studied in detail in luminal breast cancer, despite the prevalence of this subtype of mammary malignancy. Here we demonstrate that the BET bromodomain inhibitor JQ1 exerts growth-inhibitory activity in human luminal breast cancer cell lines associated with a depletion of the C-MYC oncogene, but does not alter the expression levels of the BRD4 bromodomain protein. Interestingly, expression microarray analyses indicate that, upon JQ1 administration, the antitumoral phenotype also involves downregulation of relevant breast cancer oncogenes such as the Breast Carcinoma-Amplified Sequence 1 (BCAS1) and the PDZ Domain-Containing 1 (PDZK1)...
May 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28624514/bromodomain-containing-proteins-in-prostate-cancer
#8
REVIEW
Alfonso Urbanucci, Ian G Mills
Several oncogenic factors have been involved in prostate cancer progression. However, therapeutic approaches still focus on suppression of androgen receptor (AR) signaling. In fact, whereas the full-length AR incorporates a ligand-binding domain, which has become a drug target for competitive inhibitors, other transcription factors often do not have tractable binding pockets that aid drug development. Consequently drug development efforts have turned to transcription co-regulators, often chromatin-modifying enzymes or factors that bind to epigenetic modifications to chromatin...
June 14, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28624199/engineering-next-generation-bet-independent-mlv-vectors-for-safer-gene-therapy
#9
Sara El Ashkar, Dominique Van Looveren, Franziska Schenk, Lenard S Vranckx, Jonas Demeulemeester, Jan De Rijck, Zeger Debyser, Ute Modlich, Rik Gijsbers
Retroviral vectors have shown their curative potential in clinical trials correcting monogenetic disorders. However, therapeutic benefits were compromised due to vector-induced dysregulation of cellular genes and leukemia development in a subset of patients. Bromodomain and extraterminal domain (BET) proteins act as cellular cofactors that tether the murine leukemia virus (MLV) pre-integration complex to host chromatin via interaction with the MLV integrase (IN) and thereby define the typical gammaretroviral integration distribution...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28619718/click-chemistry-enables-preclinical-evaluation-of-targeted-epigenetic-therapies
#10
Dean S Tyler, Johanna Vappiani, Tatiana Cañeque, Enid Y N Lam, Aoife Ward, Omer Gilan, Yih-Chih Chan, Antje Hienzsch, Anna Rutkowska, Thilo Werner, Anne J Wagner, Dave Lugo, Richard Gregory, Cesar Ramirez Molina, Neil Garton, Christopher R Wellaway, Susan Jackson, Laura MacPherson, Margarida Figueiredo, Sabine Stolzenburg, Charles C Bell, Colin House, Sarah-Jane Dawson, Edwin D Hawkins, Gerard Drewes, Rab K Prinjha, Raphaël Rodriguez, Paola Grandi, Mark A Dawson
The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. Here we modify BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click-chemistry and can be used as molecular probes in vitro and in vivo. Using click-proteomics and click-sequencing we explore the gene regulatory function of bromodomain containing 4 protein (BRD4) and the transcriptional changes induced by BET inhibitors. Studying mouse models of acute leukemia, we use high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments...
June 15, 2017: Science
https://www.readbyqxmd.com/read/28618269/red-blood-cell-invasion-by-the-malaria-parasite-is-coordinated-by-the-pfap2-i-transcription-factor
#11
Joana Mendonca Santos, Gabrielle Josling, Philipp Ross, Preeti Joshi, Lindsey Orchard, Tracey Campbell, Ariel Schieler, Ileana M Cristea, Manuel Llinás
Obligate intracellular parasites must efficiently invade host cells in order to mature and be transmitted. For the malaria parasite Plasmodium falciparum, invasion of host red blood cells (RBCs) is essential. Here we describe a parasite-specific transcription factor PfAP2-I, belonging to the Apicomplexan AP2 (ApiAP2) family, that is responsible for regulating the expression of genes involved in RBC invasion. Our genome-wide analysis by ChIP-seq shows that PfAP2-I interacts with a specific DNA motif in the promoters of target genes...
June 14, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28606761/inhibition-of-bromodomain-containing-protein-9-for-the-prevention-of-epigenetically-defined-drug-resistance
#12
Terry D Crawford, Steffan Vartanian, Alexandre Côté, Steve Bellon, Martin Duplessis, E Megan Flynn, Michael Hewitt, Hon-Ren Huang, James R Kiefer, Jeremy Murray, Christopher G Nasveschuk, Eneida Pardo, F Anthony Romero, Peter Sandy, Yong Tang, Alexander M Taylor, Vickie Tsui, Jian Wang, Shumei Wang, Laura Zawadzke, Brian K Albrecht, Steven R Magnuson, Andrea G Cochran, David Stokoe
Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28604107/accelerating-drug-development-for-neuroblastoma-new-drug-development-strategy-an-innovative-therapies-for-children-with-cancer-european-network-for-cancer-research-in-children-and-adolescents-and-international-society-of-paediatric-oncology-europe-neuroblastoma
#13
Lucas Moreno, Hubert Caron, Birgit Geoerger, Angelika Eggert, Gudrun Schleiermacher, Penelope Brock, Dominique Valteau-Couanet, Louis Chesler, Johannes H Schulte, Katleen De Preter, Jan Molenaar, Alexander Schramm, Martin Eilers, Tom Van Maerken, John Inge Johnsen, Michelle Garrett, Sally L George, Deborah A Tweddle, Per Kogner, Frank Berthold, Jan Koster, Giuseppe Barone, Elizabeth R Tucker, Lynley Marshall, Ralf Herold, Jaroslav Sterba, Koen Norga, Gilles Vassal, Andrew Dj Pearson
Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma...
June 12, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28595007/impact-of-target-warhead-and-linkage-vector-on-inducing-protein-degradation-comparison-of-bromodomain-and-extra-terminal-bet-degraders-derived-from-triazolodiazepine-jq1-and-tetrahydroquinoline-i-bet726-bet-inhibitor-scaffolds
#14
Kwok-Ho Chan, Michael Zengerle, Andrea Testa, Alessio Ciulli
The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation, and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead...
June 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28593508/bet-bromodomain-inhibitor-jq1-decreases-cd30-and-ccr4-expression-and-proliferation-of-cutaneous-t-cell-lymphoma-cell-lines
#15
Hiroaki Kamijo, Makoto Sugaya, Naomi Takahashi, Tomonori Oka, Tomomitsu Miyagaki, Yoshihide Asano, Shinichi Sato
Bromodomain and external domain (BET) proteins regulate cell growth, proliferation, cell cycle, and differentiation in various cancers. Therefore, they have emerged as interesting targets. The effect of BET inhibitor on cutaneous T-cell lymphoma (CTCL), however, is yet to be known. Here, we examined the effect of BET inhibitor JQ1 on four cell lines (MyLa, SeAx, Hut78 and HH cells). CTCL cell lines were treated with JQ1 and cell number, cell cycle, frequency of apoptosis, and expressions of CD25, CD30 and CCR4 on the cell surface were evaluated by flow cytometry...
June 7, 2017: Archives of Dermatological Research
https://www.readbyqxmd.com/read/28591577/androgen-receptor-deregulation-drives-bromodomain-mediated-chromatin-alterations-in-prostate-cancer
#16
Alfonso Urbanucci, Stefan J Barfeld, Ville Kytölä, Harri M Itkonen, Ilsa M Coleman, Daniel Vodák, Liisa Sjöblom, Xia Sheng, Teemu Tolonen, Sarah Minner, Christoph Burdelski, Kati K Kivinummi, Annika Kohvakka, Steven Kregel, Mandeep Takhar, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Paul Lloyd, R Jeffrey Karnes, Ashley E Ross, Edward M Schaeffer, Donald J Vander Griend, Stefan Knapp, Eva Corey, Felix Y Feng, Peter S Nelson, Fahri Saatcioglu, Karen E Knudsen, Teuvo L J Tammela, Guido Sauter, Thorsten Schlomm, Matti Nykter, Tapio Visakorpi, Ian G Mills
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect...
June 6, 2017: Cell Reports
https://www.readbyqxmd.com/read/28588073/brd4-brd2-isoform-switching-coordinates-pluripotent-exit-and-smad2-dependent-lineage-specification
#17
Rosalia Fernandez-Alonso, Lindsay Davidson, Jens Hukelmann, Michael Zengerle, Alan R Prescott, Angus Lamond, Alessio Ciulli, Gopal P Sapkota, Greg M Findlay
Pluripotent stem cells (PSCs) hold great clinical potential, as they possess the capacity to differentiate into fully specialised tissues such as pancreas, liver, neurons and cardiac muscle. However, the molecular mechanisms that coordinate pluripotent exit with lineage specification remain poorly understood. To address this question, we perform a small molecule screen to systematically identify novel regulators of the Smad2 signalling network, a key determinant of PSC fate. We reveal an essential function for BET family bromodomain proteins in Smad2 activation, distinct from the role of Brd4 in pluripotency maintenance...
June 6, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28588024/bet-inhibitors-block-the-epstein-barr-virus-lytic-cycle-at-two-distinct-steps
#18
Kristin M Keck, Stephanie A Moquin, Amanda He, Samantha G Fernandez, Jessica J Somberg, Stephanie M Liu, Delsy M Martinez, Jj L Miranda
Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle...
June 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28586718/discovery-of-a-series-of-dihydroquinoxalin-2-1h-ones-as-selective-bet-inhibitors-from-a-dual-plk1-brd4-inhibitor
#19
Jianping Hu, Yingqing Wang, Yanlian Li, Lin Xu, Danyan Cao, ShanShan Song, Mohammadali Soleimani Damaneh, Xin Wang, Tao Meng, Yue-Lei Chen, Jingkang Shen, Zehong Miao, Bing Xiong
Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy...
May 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28580303/the-role-of-bromodomain-testis-specific-factor-brdt-in-cancer-a-biomarker-and-a-possible-therapeutic-target
#20
REVIEW
Ekaterina Bourova-Flin, Florent Chuffart, Sophie Rousseaux, Saadi Khochbin
Cancer cells have recently been shown to activate hundreds of normally silent tissue-restricted genes, including a specific subset associated with cancer progression and poor prognosis. Within these genes, a class of testis-specific genes designed as cancer/testis, attracted special attention because of their oncogenic roles as well as their potential use in immunotherapy. Here we focus on one of these genes encoding the testis-specific member of the bromodomain and extra-terminal (BET) family, known as BRDT...
2017: Cell Journal
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