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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/28635318/what-structural-modifications-can-be-used-for-brd4-inhibitors-for-their-use-in-leukemia-therapy
#5
Dahong Yao, Jie Liu, Liang Ouyang
No abstract text is available yet for this article.
June 21, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28630312/uncovering-brd4-hyperphosphorylation-associated-with-cellular-transformation-in-nut-midline-carcinoma
#6
Ranran Wang, Xing-Jun Cao, Katarzyna Kulej, Wei Liu, Tongcui Ma, Margo MacDonald, Cheng-Ming Chiang, Benjamin A Garcia, Jianxin You
The epigenetic reader BRD4 plays a vital role in transcriptional regulation, cellular growth control, and cell-cycle progression. Dysregulation of BRD4 function has been implicated in the pathogenesis of a wide range of cancers. However, how BRD4 is regulated to maintain its normal function in healthy cells and how alteration of this process leads to cancer remain poorly understood. In this study, we discovered that BRD4 is hyperphosphorylated in NUT midline carcinoma and identified CDK9 as a potential kinase mediating BRD4 hyperphosphorylation...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28627048/derivatives-of-holomycin-and-cyclopropaneacetic-acid-from-streptomyces-sp-dt-a37
#7
Hui Ding, Jianan Wang, Dashan Zhang, Zhongjun Ma
On the basis of the one strain-many compounds (OSMAC) strategy, five compounds including two new holomycin derivatives (2-3), two new cyclopropaneacetic acid derivatives (4-5), together with one known compound holomycin (1) were isolated from a marine-derived bacterium Streptomyces sp. DT-A37. Their structures were elucidated using NMR and HRESIMS analyses. All these compounds were evaluated for their antimicrobial activity, cytotoxic activity, and inhibitory activity against BRD4 protein. Compound 1 exhibited potent cytotoxicity against H1975 cells with IC50 value of 1 μM, and its MIC values against Escherichia coli and Staphylococcus aureus were both 64 μM...
June 19, 2017: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/28626565/site-specific-azide-acetyllysine-photochemistry-on-epigenetic-readers-for-interactome-profiling
#8
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
#9
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/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/28591577/androgen-receptor-deregulation-drives-bromodomain-mediated-chromatin-alterations-in-prostate-cancer
#11
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
#12
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
#13
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
#14
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/28569271/heart-failure-brd4-inhibition-slows-hf-progression
#15
Dario Ummarino
No abstract text is available yet for this article.
July 2017: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/28564537/attach-pull-release-calculations-of-ligand-binding-and-conformational-changes-on-the-first-brd4-bromodomain
#16
Germano Heinzelmann, Niel M Henriksen, Michael K Gilson
Bromodomains, protein domains involved in epigenetic regulation, are able to bind small molecules with high affinity. In the present study, we report free energy calculations for the binding of seven ligands to the first BRD4 bromodomain, using the attach-pull-release (APR) method to compute the reversible work of removing the ligands from the binding site and then allowing the protein to relax conformationally. We test three different water models, TIP3P, TIP4PEw and SPC/E, as well as the GAFF and GAFF2 parameter sets for the ligands...
May 31, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28549889/synthesis-and-evaluation-of-novel-dual-brd4-hdac-inhibitors
#17
Seika Amemiya, Takao Yamaguchi, Yuichi Hashimoto, Tomomi Noguchi-Yachide
Epigenetic regulation of gene expression via histone acetylation modulates many cellular processes, including apoptosis, the cell cycle, cell growth and differentiation, and inhibitors are promising drug candidates. We have previously developed inhibitors of BRD4, which recognizes acetylated lysine residue on histones and recruits transcription elongation factor to the transcription start site, while inhibitors of histone deacetylase (HDAC), which catalyzes the removal of acetyl groups on histones, are already in clinical use for cancer treatment...
May 17, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28548929/brd4-facilitates-dna-damage-response-and-represses-cbx5-heterochromatin-protein-1-hp1
#18
Georgios Pongas, Marianne K Kim, Dong J Min, Carrie D House, Elizabeth Jordan, Natasha Caplen, Sirisha Chakka, Joyce Ohiri, Michael J Kruhlak, Christina M Annunziata
Ovarian cancer (OC) is a heterogeneous disease characterized by defective DNA repair. Very few targets are universally expressed in the high grade serous (HGS) subtype. We previously identified that CHK1 was overexpressed in most of HGSOC. Here, we sought to understand the DNA damage response (DDR) to CHK1 inhibition and increase the anti-tumor activity of this pathway. We found BRD4 suppression either by siRNA or BRD4 inhibitor JQ1 enhanced the cytotoxicity of CHK1 inhibition. Interestingly, BRD4 was amplified and/or upregulated in a subset of HGSOC with statistical correlation to overall survival...
May 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28545522/brd4-inhibition-suppresses-cell-growth-migration-and-invasion-of-salivary-adenoid-cystic-carcinoma
#19
Limei Wang, Xiuyin Wu, Ruolin Wang, Chengzhe Yang, Zhi Li, Cunwei Wang, Fenghe Zhang, Pishan Yang
BACKGROUND: Bromodomain-containing protein 4 (BRD4) inhibition is a new therapeutic strategy for many malignancies. In this study, we aimed to explore the effect of BRD4 inhibition by JQ1 on in vitro cell growth, migration and invasion of salivary adenoid cystic carcinoma (SACC). METHODS: The human normal epithelial cells and SACC cells (ACC-LM and ACC-83) were treated with JQ1 at concentrations of 0, 0.1, 0.5 or 1 μM. Cell Counting Kit-8 (CCK-8) assay was performed to evaluate cell proliferation...
May 25, 2017: Biological Research
https://www.readbyqxmd.com/read/28535045/bet-bromodomain-inhibitors-with-one-step-synthesis-discovered-from-virtual-screen
#20
Alex M Ayoub, Laura M L Hawk, Ryan J Herzig, Jiewei Jiang, Andrea J Wisniewski, Clifford T Gee, Peiliang Zhao, Jin-Yi Zhu, Norbert Berndt, Nana K Offei-Addo, Thomas G Scott, Jun Qi, James E Bradner, Timothy R Ward, Ernst Schönbrunn, Gunda I Georg, William C K Pomerantz
Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity...
June 7, 2017: Journal of Medicinal Chemistry
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