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Bromodomain inhibitors

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https://www.readbyqxmd.com/read/28935884/muscle-hypertrophy-in-hypoxia-with-inflammation-is-controlled-by-bromodomain-and-extra-terminal-domain-proteins
#1
Clovis Chabert, Saadi Khochbin, Sophie Rousseaux, Rebecca Furze, Nicholas Smithers, Rab Prinjha, Uwe Schlattner, Christophe Pison, Hervé Dubouchaud
Some of the Chronic Obstructive Pulmonary Disease (COPD) patients engaged in exercise-based muscle rehabilitation programs are unresponsive. To unravel the respective role of chronic hypoxia and pulmonary inflammation on soleus muscle hypertrophic capacities, we challenged male Wistar rats to repeated lipopolysaccharide instillations, associated or not with a chronic hypoxia exposure. Muscle hypertrophy was initiated by bilateral ablation of soleus agonists 1 week before sacrifice. To understand the role played by the histone acetylation, we also treated our animals with an inhibitor of bromodomains and extra terminal proteins (I-BET) during the week after surgery...
September 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28931940/brd4-regulates-adiponectin-gene-induction-by-recruiting-the-p-tefb-complex-to-the-transcribed-region-of-the-gene
#2
Naoko Sakurai, Yuko Inamochi, Takuya Inoue, Natsuyo Hariya, Musashi Kawamura, Masami Yamada, Anup Dey, Akira Nishiyama, Takeo Kubota, Keiko Ozato, Toshinao Goda, Kazuki Mochizuki
We previously reported that induction of the adipocyte-specific gene adiponectin (Adipoq) during 3T3-L1 adipocyte differentiation is closely associated with epigenetic memory histone H3 acetylation on the transcribed region of the gene. We used 3T3-L1 adipocytes and Brd4 heterozygous mice to investigate whether the induction of Adipoq during adipocyte differentiation is regulated by histone acetylation and the binding protein bromodomain containing 4 (BRD4) on the transcribed region. Depletion of BRD4 by shRNA and inhibition by (+)-JQ1, an inhibitor of BET family proteins including BRD4, reduced Adipoq expression and lipid droplet accumulation in 3T3-L1 adipocytes...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28930680/systematic-kinase-inhibitor-profiling-identifies-cdk9-as-a-synthetic-lethal-target-in-nut-midline-carcinoma
#3
Johannes Brägelmann, Marcel A Dammert, Felix Dietlein, Johannes M Heuckmann, Axel Choidas, Stefanie Böhm, André Richters, Debjit Basu, Verena Tischler, Carina Lorenz, Peter Habenberger, Zhizhou Fang, Sandra Ortiz-Cuaran, Frauke Leenders, Jan Eickhoff, Uwe Koch, Matthäus Getlik, Martin Termathe, Muhammad Sallouh, Zoltán Greff, Zoltán Varga, Hyatt Balke-Want, Christopher A French, Martin Peifer, H Christian Reinhardt, László Örfi, György Kéri, Sascha Ansén, Lukas C Heukamp, Reinhard Büttner, Daniel Rauh, Bert M Klebl, Roman K Thomas, Martin L Sos
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28916223/bet-bromodomain-inhibitors-modulate-epigenetic-patterns-at-the-diacylglycerol-kinase-alpha-enhancer-associated-with-radiation-induced-fibrosis
#4
Gintvile Valinciute, Christoph Weigel, Marlon R Veldwijk, Christopher C Oakes, Carsten Herskind, Frederik Wenz, Christoph Plass, Peter Schmezer, Odilia Popanda
BACKGROUND AND PURPOSE: Fibrosis is a frequent adverse effect of radiotherapy and no effective treatments are currently available to prevent or reverse fibrotic disease. We have previously identified altered epigenetic patterns at a gene enhancer of the diacylglycerol kinase alpha (DGKA) locus in normal skin fibroblasts derived from fibrosis patients. An open chromatin pattern related to radiation-inducibility of DGKA is associated with onset of radiation-induced fibrosis. Here, we explore epigenetic modulation of DGKA as a way to mitigate predisposition to fibrosis...
September 12, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28901664/pharmacophore-based-virtual-screening-molecular-docking-molecular-dynamics-simulation-and-biological-evaluation-for-the-discovery-of-novel-brd4-inhibitors
#5
Guoyi Yan, Manzhou Hou, Jiang Luo, Chunlan Pu, Xueyan Hou, Suke Lan, Rui Li
Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors by using pharmacophore based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules out of twelve hits were found to be active in bioactivity tests...
September 13, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28892380/gne-781-a-highly-advanced-potent-and-selective-bromodomain-inhibitor-of-cyclic-adenosine-monophosphate-response-element-binding-protein-binding-protein-cbp
#6
F Anthony Romero, Jeremy Murray, Kwong Wah Lai, Vickie Tsui, Brian K Albrecht, Le An, Maureen H Beresini, Gladys de Leon Boenig, Sarah M Bronner, Emily W Chan, Kevin X Chen, Zhongguo Chen, Edna F Choo, Kyle Clagg, Kevin Clark, Terry D Crawford, Patrick Cyr, Denise de Almeida Nagata, Karen E Gascoigne, Jane L Grogan, Georgia Hatzivassiliou, Wei Huang, Thomas L Hunsaker, Susan Kaufman, Stefan G Koenig, Ruina Li, Yingjie Li, Xiaorong Liang, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jonathan Maher, Colin Masui, Mark Merchant, Yingqing Ran, Alexander M Taylor, John Wai, Fei Wang, Xiaocang Wei, Dong Yu, Bing-Yan Zhu, Xiaoyu Zhu, Steven Magnuson
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28891793/regulation-of-the-glucocorticoid-receptor-via-a-bet-dependent-enhancer-drives-antiandrogen-resistance-in-prostate-cancer
#7
Neel Shah, Ping Wang, John Wongvipat, Wouter R Karthaus, Wassim Abida, Joshua Armenia, Shira Rockowitz, Yotam Drier, Bradley E Bernstein, Henry W Long, Matthew L Freedman, Vivek K Arora, Deyou Zheng, Charles L Sawyers
In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals...
September 11, 2017: ELife
https://www.readbyqxmd.com/read/28884163/identification-of-a-novel-class-of-brd4-inhibitors-by-computational-screening-and-binding-simulations
#8
Bryce K Allen, Saurabh Mehta, Stuart W J Ember, Jin-Yi Zhu, Ernst Schönbrunn, Nagi G Ayad, Stephan C Schürer
Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank...
August 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/28881723/association-of-high-microvessel-%C3%AE-v%C3%AE-3-and-low-pten-with-poor-outcome-in-stage-3-neuroblastoma-rationale-for-using-first-in-class-dual-pi3k-brd4-inhibitor-sf1126
#9
Anat Erdreich-Epstein, Alok R Singh, Shweta Joshi, Francisco M Vega, Pinzheng Guo, Jingying Xu, Susan Groshen, Wei Ye, Melissa Millard, Mihaela Campan, Guillermo Morales, Joseph R Garlich, Peter W Laird, Robert C Seeger, Hiroyuki Shimada, Donald L Durden
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αvβ3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αvβ3 was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in αvβ3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881673/bromodomain-inhibition-shows-antitumoral-activity-in-mice-and-human-luminal-breast-cancer
#10
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)...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28870238/bet-bromodomain-inhibitors-and-agonists-of-the-beta-2-adrenergic-receptor-identified-in-screens-for-compounds-that-inhibit-dux4-expression-in-fshd-muscle-cells
#11
Amy E Campbell, Jonathan Oliva, Matthew P Yates, Jun Wen Zhong, Sean C Shadle, Lauren Snider, Nikita Singh, Shannon Tai, Yosuke Hiramuki, Rabi Tawil, Silvère M van der Maarel, Stephen J Tapscott, Francis M Sverdrup
BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. METHODS: We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures...
September 4, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28862840/discovery-of-inhibitors-of-four-bromodomains-by-fragment-anchored-ligand-docking
#12
Jean-Rémy Marchand, Andrea Dalle Vedove, Graziano Lolli, Amedeo Caflisch
The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. Here we present an updated version of ALTA-VS with a broader range of potential applications. The evaluation of binding energy makes use of a classical force field with implicit solvent in the continuum dielectric approximation...
September 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28854735/brd4-inhibitors-block-telomere-elongation
#13
Steven Wang, Alexandra M Pike, Stella S Lee, Margaret A Strong, Carla J Connelly, Carol W Greider
Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase...
August 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28846825/use-of-fluorine-pseudocontact-shifts-to-characterize-the-protein-ligand-interaction-mode-in-the-limit-of-nmr-intermediate-exchange
#14
Jia Gao, E Liang, Rongsheng Ma, Fudong Li, Yiyang Liu, Jiuyang Liu, Ling Jiang, Conggang Li, Haiming Dai, Jihui Wu, Xuncheng Su, Wei He, Ke Ruan
The characterization of protein-ligand interaction modes becomes recalcitrant in the NMR intermediate exchange regime as the interface resonances are broadened beyond detection. Here, we determined the 19F low-populated bound-state pseudocontact shifts (PCSs) of mono- and di-fluorinated inhibitors of the BRM bromodomain using a highly-skewed protein/ligand ratio. The bound-state 19F PCSs were retrieved from 19F chemical exchange saturation transfer (CEST) in the presence of the lanthanide-labeled protein, which was termed the 19F PCS-CEST approach...
August 28, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28838216/bet-inhibitors-a-novel-epigenetic-approach
#15
D B Doroshow, J P Eder, P M LoRusso
Epigenetics has been defined as 'the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.' Currently, several classes of anticancer drugs function at the epigenetic level, including inhibitors of DNA methyltransferase, histone deacetylase (HDAC), lysine-specific demethylase 1, zeste homolog 2, and bromodomain and extra-terminal motif (BET) proteins.BET proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation...
August 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28835800/design-and-optimization-of-benzopiperazines-as-potent-inhibitors-of-bet-bromodomains
#16
David S Millan, Katherine J Kayser-Bricker, Matthew W Martin, Adam C Talbot, Shawn E R Schiller, Torsten Herbertz, Grace L Williams, George P Luke, Stephen Hubbs, Monica A Alvarez Morales, Daniel Cardillo, Paul Troccolo, Rachel L Mendes, Crystal McKinnon
A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability...
August 10, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28821780/selective-inhibition-mechanism-of-rvx-208-to-the-second-bromodomain-of-bromo-and-extraterminal-proteins-insight-from-microsecond-molecular-dynamics-simulations
#17
Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Elaine Lai-Han Leung, Liang Liu, Xiaojun Yao
RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the first and second bromodomains (BD1 and BD2), the detailed selectivity mechanism of RVX-208 towards BD2 over BD1 is still unknown. To elucidate selective inhibition mechanism of RVX-208 to BD2, microsecond molecular dynamics simulations were performed in this study for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with and without RVX-208, respectively...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28819026/therapeutic-targeting-of-the-cbp-p300-bromodomain-blocks%C3%A2-the-growth-of-castration-resistant-prostate-cancer
#18
Lingyan Jin, Jesse Garcia, Emily Chan, Cecile de la Cruz, Ehud Segal, Mark Merchant, Samir Kharbanda, Ryan Raisner, Peter M Haverty, Zora Modrusan, Justin Ly, Edna Choo, Susan Kaufman, Maureen H Beresini, F Anthony Romero, Steven Magnuson, Karen E Gascoigne
Resistance invariably develops to anti-androgen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here we report that the transcriptional co-activator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression...
August 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28813519/expression-and-inhibition-of-brd4-ezh2-and-top2a-in-neurofibromas-and-malignant-peripheral-nerve-sheath-tumors
#19
Azadeh Amirnasr, Rob M Verdijk, Patricia F van Kuijk, Walter Taal, Stefan Sleijfer, Erik A C Wiemer
Malignant peripheral nerve sheath tumors (MPNST) are rare, highly aggressive sarcomas that can occur spontaneously or from pre-existing plexiform neurofibromas in neurofibromatosis type1 (NF1) patients. MPNSTs have high local recurrence rates, metastasize easily, are generally resistant to therapeutic intervention and frequently fatal for the patient. Novel targeted therapeutic strategies are urgently needed. Standard treatment for patients presenting with advanced disease is doxorubicin based chemotherapy which inhibits the actions of the enzyme topoisomerase IIα (TOP2A)...
2017: PloS One
https://www.readbyqxmd.com/read/28807940/mitotic-vulnerability-in-triple-negative-breast-cancer-associated-with-lin9-is-targetable-with-bet-inhibitors
#20
Jennifer M Sahni, Sylvia S Gayle, Bryan Webb, Kristen L Weber-Bonk, Darcie D Seachrist, Salendra Singh, Steven T Sizemore, Nicole A Restrepo, Gurkan Bebek, Peter Scacheri, Vinay Varadan, Matthew K Summers, Ruth A Keri
Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of Bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe...
August 14, 2017: Cancer Research
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