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https://www.readbyqxmd.com/read/29656650/discovery-of-tetrahydroquinoxalines-as-bromodomain-and-extra-terminal-domain-bet-inhibitors-with-selectivity-for-the-second-bromodomain
#1
Robert P Law, Stephen J Atkinson, Paul Bamborough, Chun-Wa Chung, Emmanuel H Demont, Laurie J Gordon, Matthew Lindon, Rab K Prinjha, Allan J B Watson, David Jonathan Hirst
The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains, BRD2, BRD3, BRD4 and BRDT, each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains...
April 15, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29608786/dna-methylation-of-the-brd2-promoter-is-associated-with-juvenile-myoclonic-epilepsy-in-caucasians
#2
Shilpa Pathak, James Miller, Emily C Morris, William C L Stewart, David A Greenberg
OBJECTIVE: Juvenile myoclonic epilepsy (JME) is a common adolescent-onset genetic generalized epilepsy (GGE) syndrome. Multiple linkage and association studies have found that BRD2 influences the expression of JME. The BRD2-JME connection is further corroborated by our murine model; Brd2 haploinsufficiency produces characteristics that typify the clinical hallmarks of JME. Neither we, nor several large-scale studies of JME, found JME-related BRD2 coding mutations. Therefore, we investigated noncoding BRD2 regions, seeking the origin of BRD2's JME influence...
April 2, 2018: Epilepsia
https://www.readbyqxmd.com/read/29605436/the-role-of-za-channel-water-mediated-interactions-in-the-design-of-bromodomain-selective-bet-inhibitors
#3
Nagakumar Bharatham, Peter J Slavish, Brandon M Young, Anang A Shelat
The Bromodomain and Extra-Terminal domain (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains. One position located in the ZA loop has unique properties...
March 22, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29555663/targeting-bromodomain-and-extra-terminal-bet-family-proteins-in-castration-resistant-prostate-cancer-crpc
#4
Jonathan Welti, Adam Sharp, Wei Yuan, David I Dolling, Daniel Nava Rodrigues, Ines Figueiredo, Veronica Gil, Antje Neeb, Matthew Clarke, George Seed, Mateus Crespo, Semini Sumanasuriya, Jian Ning, Eleanor Knight, Jeffrey C Francis, Ashley Hughes, Wendy S Halsey, Alec Paschalis, Ram S Mani, Ganesh V Raj, Steve Plymate, Suzanne Carreira, Gunther Boysen, Arul M Chinnaiyan, Amanda Swain, Johann S de Bono
PURPOSE:  Persistent androgen receptor (AR) signaling drives castration resistant prostate cancer (CRPC) and confers resistance to AR targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. EXPERIMENTAL DESIGN:  We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models...
March 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29505757/lyar-mediated-recruitment-of-brd2-to-the-chromatin-attenuates-nanog-downregulation-following-induction-of-differentiation
#5
Noelia Luna-Peláez, Mario García-Domínguez
During development, cellular differentiation programs need of tight regulation for proper display of the activity of multiple factors in time and space. Chromatin adaptors of the BET family (Brd2, Brd3, Brd4 and Brdt in vertebrates) are transcription co-regulators tightly associated with the progression of the cell cycle. A key question regarding their function is whether they work as part of the general transcription machinery or, on the contrary, they are precisely recruited to the chromatin through specific transcription factors...
March 2, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29493812/bet-proteins-in-abnormal-metabolism-inflammation-and-the-breast-cancer-microenvironment
#6
REVIEW
Guillaume P Andrieu, Jordan S Shafran, Jude T Deeney, Kishan R Bharadwaj, Annapoorni Rangarajan, Gerald V Denis
Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling. The pathways by which tumor cells evade immune surveillance, immune therapies, and take advantage of antitumor immunity are poorly understood, but likely depend on metabolic inflammation in the microenvironment...
March 1, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29483155/a-mechanism-for-epigenetic-control-of-dna-replication
#7
Courtney G Sansam, Katarzyna Pietrzak, Blanka Majchrzycka, Maciej A Kerlin, Jingrong Chen, Susannah Rankin, Christopher L Sansam
DNA replication origins in hyperacetylated euchromatin fire preferentially during early S phase. However, how acetylation controls DNA replication timing is unknown. TICRR/TRESLIN is an essential protein required for the initiation of DNA replication. Here, we report that TICRR physically interacts with the acetyl-histone binding bromodomain (BRD) and extraterminal (BET) proteins BRD2 and BRD4. Abrogation of this interaction impairs TICRR binding to acetylated chromatin and disrupts normal S-phase progression...
February 1, 2018: Genes & Development
https://www.readbyqxmd.com/read/29448097/selective-degradation-of-bet-proteins-with-dbet1-a-proteolysis-targeting-chimera-potently-reduces-pro-inflammatory-responses-in-lipopolysaccharide-activated-microglia
#8
Kelly M DeMars, Changjun Yang, Carolina I Castro-Rivera, Eduardo Candelario-Jalil
Bromodomain and extraterminal (BET) proteins are essential to pro-inflammatory gene transcription. The BET family proteins, BRD2, BRD3, BRD4, and testis-specific BRDT, couple chromatin remodeling to gene transcription, acting as histone acetyltransferases, scaffolds for transcription complexes, and markers of histone acetylation. To initiate an inflammatory response, cells undergo de novo gene transcription requiring histone-modifying proteins to make DNA wrapped around histones more or less readily available to transcription complexes...
February 12, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29437854/bet-proteins-exhibit-transcriptional-and-functional-opposition-in-the-epithelial-to-mesenchymal-transition
#9
Guillaume P Andrieu, Gerald V Denis
Transcriptional programs in embryogenesis and cancer, such as the epithelial-to-mesenchymal transition (EMT), ensure cellular plasticity, an essential feature of carcinoma progression. As effectors of signal transduction, the bromodomain and extraterminal (BET) proteins are well suited to support plasticity because they function as co-activators or co-repressors of mammalian transcriptomes. Here, using both hormone-sensitive and triple-negative breast cancer (TNBC) model systems, we systematically altered EMT transcriptional profiles by manipulating individual BET proteins and found that BRD2 positively regulates EMT, whereas BRD3 and BRD4 repress this program...
February 7, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29399399/bromodomain-inhibition-exerts-its-therapeutic-potential-in-malignant-pleural-mesothelioma-by-promoting-immunogenic-cell-death-and-changing-the-tumor-immune-environment
#10
Chiara Riganti, Marcello Francesco Lingua, Iris Chiara Salaroglio, Chiara Falcomatà, Luisella Righi, Deborah Morena, Francesca Picca, Daniele Oddo, Joanna Kopecka, Monica Pradotto, Roberta Libener, Sara Orecchia, Paolo Bironzo, Valentina Comunanza, Federico Bussolino, Silvia Novello, Giorgio Vittorio Scagliotti, Federica Di Nicolantonio, Riccardo Taulli
Systemic treatment of malignant pleural mesothelioma (MPM) is moderately active for the intrinsic pharmacological resistance of MPM cell and its ability to induce an immune suppressive environment. Here we showed that the expression of bromodomain (BRD) proteins BRD2, BRD4 and BRD9 was significantly higher in human primary MPM cells compared to normal mesothelial cells (HMC). Nanomolar concentrations of bromodomain inhibitors (BBIs) JQ1 or OTX015 impaired patient-derived MPM cell proliferation and induced cell-cycle arrest without affecting apoptosis...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29196562/the-role-of-bromodomain-and-extraterminal-motif-bet-proteins-in-chromatin-structure
#11
Sarah C Hsu, Gerd A Blobel
Bromodomain and extraterminal motif (BET) proteins have been widely investigated for their roles in gene regulation and their potential as therapeutic targets in cancer. Pharmacologic BET inhibitors target the conserved bromodomain-acetyllysine interaction and do not distinguish between BRD2, BRD3, and BRD4. Thus, comparatively little is known regarding the distinct roles played by individual family members, as well as the underlying mechanisms that drive the transcriptional effects of BET inhibitors. Here we review studies regarding the contributions of BET proteins to genome structure and function, including recent work identifying a role for BRD2 as a component of functional and physical chromatin domain boundaries...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/29180574/mir-126-5p-promotes-retinal-endothelial-cell-survival-through-setd5-regulation-in-neurons
#12
Gaëlle Villain, Loïc Poissonnier, Baraa Noueihed, Gaëlle Bonfils, Jose Carlos Rivera, Sylvain Chemtob, Fabrice Soncin, Virginie Mattot
MicroRNAs are key regulators of angiogenesis, as illustrated by the vascular defects observed in miR-126-deficient animals. The miR-126 duplex gives rise to two mature microRNAs (miR-126-3p and -5p). The vascular defects in these mutant animals were attributed to the loss of miR-126-3p but the role of miR-126-5p during normal angiogenesis in vivo remains unknown. Here, we show that miR-126-5p is expressed in endothelial cells but also by retinal ganglion cells (RGCs) of the mouse postnatal retina and participates in protecting endothelial cells from apoptosis during the establishment of the retinal vasculature...
January 8, 2018: Development
https://www.readbyqxmd.com/read/29170024/exploiting-a-water-network-to-achieve-enthalpy-driven-bromodomain-selective-bet-inhibitors
#13
William R Shadrick, Peter J Slavish, Sergio C Chai, Brett Waddell, Michele Connelly, Jonathan A Low, Cynthia Tallant, Brandon M Young, Nagakumar Bharatham, Stefan Knapp, Vincent A Boyd, Marie Morfouace, Martine F Roussel, Taosheng Chen, Richard E Lee, R Kiplin Guy, Anang A Shelat, Philip M Potter
Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby...
January 1, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29149598/harnessing-bet-inhibitor-sensitivity-reveals-amigo2-as-a-melanoma-survival-gene
#14
Barbara Fontanals-Cirera, Dan Hasson, Chiara Vardabasso, Raffaella Di Micco, Praveen Agrawal, Asif Chowdhury, Madeleine Gantz, Ana de Pablos-Aragoneses, Ari Morgenstern, Pamela Wu, Dan Filipescu, David Valle-Garcia, Farbod Darvishian, Jae-Seok Roe, Michael A Davies, Christopher R Vakoc, Eva Hernando, Emily Bernstein
Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29082287/flow-cytometric-analysis-of-hiv-1-transcriptional-activity-in-response-to-shrna-knockdown-in-a2-and-a72-j-lat-cell-lines
#15
Daniela Boehm, Melanie Ott
The main obstacle to eradicating HIV-1 from patients is post-integration latency (Finzi et al. , 1999). Antiretroviral treatments target only actively replicating virus, while latent infections that have low or no transcriptional activity remain untreated (Sedaghat et al. , 2007). To eliminate viral reservoirs, one strategy focuses on reversing HIV-1 latency via 'shock and kill' (Deeks, 2012). The basis of this strategy is to overcome the molecular mechanisms of HIV-1 latency by therapeutically inducing viral gene and protein expression under antiretroviral therapy and to cause selective cell death via the lytic properties of the virus, or the immune system now recognizing the infected cells...
June 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29077715/protein-dynamics-and-structural-waters-in-bromodomains
#16
Xiaoxiao Zhang, Kai Chen, Yun-Dong Wu, Olaf Wiest
Bromodomains are epigenetic readers of acetylated lysines that are integral parts of histone tails. The 61 bromodomains in humans are structurally highly conserved but specifically bind to widely varying recognition motifs, suggesting that dynamic rather than static factors are responsible for recognition selectivity. To test this hypothesis, the dynamics of the binding sites and structural water molecules of four bromodomains (ATAD2, BAZ2B, BRD2(1) and CREBBP) representing four different subtypes is studied with 1 μs MD simulations using the RSFF2 force field...
2017: PloS One
https://www.readbyqxmd.com/read/29018219/spatially-restricted-loading-of-brd2-at-dna-double-strand-breaks-protects-h4-acetylation-domains-and-promotes-dna-repair
#17
Ozge Gursoy-Yuzugullu, Chelsea Carman, Brendan D Price
The n-terminal tail of histone H4 recruits repair proteins, including 53BP1, to DNA double-strand breaks (DSB) and undergoes dynamic acetylation during DSB repair. However, how H4 acetylation (H4Ac) recruits repair proteins and reorganizes chromatin during DNA repair is unclear. Here, we show that the bromodomain protein BRD2 is recruited to DSBs. This recruitment requires binding of BRD2's tandem bromodomains to H4Ac, which is generated at DSBs by the Tip60/KAT5 acetyltransferase. Binding of BRD2 to H4Ac protects the underlying acetylated chromatin from attack by histone deacetylases and allows acetylation to spread along the flanking chromatin...
October 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28983974/molecular-design-of-stat3-derived-peptide-selectivity-between-bet-proteins-brd2-and-brd4-in-ovarian-cancer
#18
Lixia Zhu, Xi Ding
Stat3 signaling has been recognized as a potential therapeutic target of human ovarian cancer. The signaling is transducted through the peptide-medicated interaction of Stat3 with BET family members Brd2 and Brd4 -- 2 highly homologous proteins involved in differential downstream pathways. Here, we reported a successful design of peptide selectivity between the Brd2 and Brd4. The design resulted in 3 linear peptides SMSLQCXYLGVA, QSKVLTXSYWGA, and RQCNLGXLYMNY with high or moderate selectivity for Brd2 over Brd4 (S = 3...
February 2018: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28955774/unveiling-the-folding-mechanism-of-the-bromodomains
#19
Maria Petrosino, Daniela Bonetti, Alessandra Pasquo, Laura Lori, Roberta Chiaraluce, Valerio Consalvi, Carlo Travaglini-Allocatelli
Bromodomains (BRDs) are small protein domains often present in large multidomain proteins involved in transcriptional regulation in eukaryotic cells. They currently represent valuable targets for the development of inhibitors of aberrant transcriptional processes in a variety of human diseases. Here we report urea-induced equilibrium unfolding experiments monitored by circular dichroism (CD) and fluorescence on two structurally similar BRDs: BRD2(2) and BRD4(1), showing that BRD4(1) is more stable than BRD2(2)...
September 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28949335/the-bet-brd-inhibitor-jq1-improves-brain-plasticity-in-wt-and-app-mice
#20
E Benito, B Ramachandran, H Schroeder, G Schmidt, H Urbanke, S Burkhardt, V Capece, C Dean, A Fischer
Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease...
September 26, 2017: Translational Psychiatry
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