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Bromodomain inhibitors

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https://www.readbyqxmd.com/read/28731328/bisphosphonate-functionalized-hydroxyapatite-nanoparticles-for-the-delivery-of-the-bromodomain-inhibitor-jq1-in-the-treatment-of-osteosarcoma
#1
Victoria Wu, Jarrett Mickens, Vuk Uskokovic
Osteosarcoma (OS) is one of the most common neoplasia among children and its survival statistics have been stagnating since the combinatorial anticancer therapy triad was first introduced. Here we report on the assessment of the effect of hydroxyapatite (HAp) nanoparticles loaded with medronate, the simplest bisphosphonate, as a bone-targeting agent and JQ1, a small-molecule bromodomain inhibitor, as a chemotherapeutic in different 2D and 3D K7M2 OS in vitro models. Both additives decreased the crystallinity of HAp, but the effect was more intense for medronate because of its higher affinity for HAp...
July 21, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28724615/glioblastoma-cellular-cross-talk-converges-on-nf-%C3%AE%C2%BAb-to-attenuate-egfr-inhibitor-sensitivity
#2
Ciro Zanca, Genaro R Villa, Jorge A Benitez, Amy Haseley Thorne, Tomoyuki Koga, Matteo D'Antonio, Shiro Ikegami, Jianhui Ma, Antonia D Boyer, Afsheen Banisadr, Nathan M Jameson, Alison D Parisian, Olesja V Eliseeva, Gabriela F Barnabe, Feng Liu, Sihan Wu, Huijun Yang, Jill Wykosky, Kelly A Frazer, Vladislav V Verkhusha, Maria G Isaguliants, William A Weiss, Timothy C Gahman, Andrew K Shiau, Clark C Chen, Paul S Mischel, Webster K Cavenee, Frank B Furnari
In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs)...
July 19, 2017: Genes & Development
https://www.readbyqxmd.com/read/28714688/design-of-a-chemical-probe-for-the-bromodomain-and-plant-homeodomain-finger-containing-brpf-family-of-proteins
#3
Niall Igoe, Elliott D Bayle, Cynthia Tallant, Oleg Fedorov, Julia C Meier, Pavel Savitsky, Catherine Rogers, Yannick Morias, Sarah Scholze, Helen Boyd, Danen Cunoosamy, David M Andrews, Anne Cheasty, Paul E Brennan, Susanne Müller, Stefan Knapp, Paul V Fish
The bromodomain and PHD finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRD1 over BRPF3, whereas binding to BRD9 was weaker. 16 has excellent selectivity over non-class IV BRD proteins. Target engagement of BRPF1B and BRD1 with 16 was demonstrated in nanoBRET and FRAP assays...
July 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28714212/fragment-based-drug-discovery-in-the-bromodomain-and-extra-terminal-domain-family
#4
REVIEW
Mostafa Radwan, Rabah Serya
Bromodomain and extra-terminal domain (BET) inhibition has emerged recently as a potential therapeutic target for the treatment of many human disorders such as atherosclerosis, inflammatory disorders, chronic obstructive pulmonary disease (COPD), some viral infections, and cancer. Since the discovery of the two potent inhibitors, I-BET762 and JQ1, different research groups have used different techniques to develop novel potent and selective inhibitors. In this review, we will be concerned with the trials that used fragment-based drug discovery (FBDD) approaches to discover or optimize BET inhibitors, also showing fragments that can be further optimized in future projects to reach novel potent BET inhibitors...
July 17, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28696689/correction-to-bet-bromodomain-inhibitors-with-one-step-synthesis-discovered-from-virtual-screen
#5
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
No abstract text is available yet for this article.
July 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28696179/insights-into-the-crystal-structure-of-brd2-bd2-phenanthridinone-complex-and-theoretical-studies-on-phenanthridinone-analogs
#6
Shruti Mathur, Prashant Deshmukh, Shailesh Tripathi, Palaniappan Marimuthu, Balasundaram Padmanbhan
BET (Bromodomain and Extra-terminal) family proteins recognize the acetylated histone code on chromatin and participate in downstream processes like DNA replication, modification, and repair. As part of epigenetic approaches, BRD2 and BRD4 were identified as putative targets, for the management of chronic diseases. We have recently reported the discovery of a new scaffold of the phenanthridinone based inhibitor (L10) of the second bromodomain of BRD2 (BRD2-BD2). Here, we present the crystal structure of the BRD2-BD2, refined to 1...
July 11, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28694331/transcriptional-elongation-control-of-the-hbv-cccdna-transcription-by-super-elongation-complex-sec-and-brd4
#7
Joel Celio Francisco, Qian Dai, Zhuojuan Luo, Yan Wang, Roxanne Hui-Heng Chong, Yee Joo Tan, Wei Xie, Guan-Huei Lee, Chengqi Lin
Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of HBV life cycle. However, factors controlling the HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the Super Elongation Complex (SEC) bind to the HBV genome...
July 10, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28684431/convergent-roles-of-atf3-and-csl-in-chromatin-control-of-cancer-associated-fibroblast-activation
#8
Dong Eun Kim, Maria-Giuseppina Procopio, Soumitra Ghosh, Seung-Hee Jo, Sandro Goruppi, Francesco Magliozzi, Pino Bordignon, Victor Neel, Paolo Angelino, G Paolo Dotto
Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes...
July 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28673542/bet-bromodomain-proteins-function-as-master-transcription-elongation-factors-independent-of-cdk9-recruitment
#9
Georg E Winter, Andreas Mayer, Dennis L Buckley, Michael A Erb, Justine E Roderick, Sarah Vittori, Jaime M Reyes, Julia di Iulio, Amanda Souza, Christopher J Ott, Justin M Roberts, Rhamy Zeid, Thomas G Scott, Joshiawa Paulk, Kate Lachance, Calla M Olson, Shiva Dastjerdi, Sophie Bauer, Charles Y Lin, Nathanael S Gray, Michelle A Kelliher, L Stirling Churchman, James E Bradner
Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation...
June 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28663582/bet-protein-proteolysis-targeting-chimera-protac-exerts-potent-lethal-activity-against-mantle-cell-lymphoma-cells
#10
B Sun, W Fiskus, Y Qian, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, D T Saenz, C P Mill, A J Nowak, N Jain, L Zhang, M Wang, J D Khoury, C Coarfa, C M Crews, K N Bhalla
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28656888/the-complex-of-trip-br1-and-xiap-ubiquitinates-and-degrades-multiple-adenylyl-cyclase-isoforms
#11
Wenbao Hu, Xiaojie Yu, Zhengzhao Liu, Ying Sun, Xibing Chen, Xin Yang, Xiaofen Li, Wai Kwan Lam, Yuanyuan Duan, Xu Cao, Hermann Steller, Kai Liu, Pingbo Huang
Adenylyl cyclases (ACs) generate cAMP, a second messenger of utmost importance that regulates a vast array of biological processes in all kingdoms of life. However, almost nothing is known about how AC activity is regulated through protein degradation mediated by ubiquitination or other mechanisms. Here, we show that transcriptional regulator interacting with the PHD-bromodomain 1 (TRIP-Br1, Sertad1), a newly identified protein with poorly characterized functions, acts as an adaptor that bridges the interaction of multiple AC isoforms with X-linked inhibitor of apoptosis protein (XIAP), a RING-domain E3 ubiquitin ligase...
June 28, 2017: ELife
https://www.readbyqxmd.com/read/28653617/replication-study-inhibition-of-bet-recruitment-to-chromatin-as-an-effective-treatment-for-mll-fusion-leukaemia
#12
Xiaochuan Shan, Juan Jose Fung, Alan Kosaka, Gwenn Danet-Desnoyers
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fung et al., 2015), that described how we intended to replicate selected experiments from the paper "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia" (Dawson et al., 2011). Here, we report the results of those experiments. We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the BET bromodomain inhibitor I-BET151 resulted in selective growth inhibition, whereas treatment of leukaemia cells harboring a different oncogenic driver (K-562 cell line) did not result in selective growth inhibition; this is similar to the findings reported in the original study (Figure 2A and Supplementary Figure 11A,B; Dawson et al...
June 27, 2017: ELife
https://www.readbyqxmd.com/read/28653353/preclinical-evaluation-of-the-bet-bromodomain-inhibitor-bay-1238097-for-the-treatment-of-lymphoma
#13
Elena Bernasconi, Eugenio Gaudio, Pascale Lejeune, Chiara Tarantelli, Luciano Cascione, Ivo Kwee, Filippo Spriano, Andrea Rinaldi, Afua A Mensah, Elaine Chung, Anastasios Stathis, Stephan Siegel, Norbert Schmees, Matthias Ocker, Emanuele Zucca, Bernard Haendler, Francesco Bertoni
The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel bromodomain and extra-terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti-proliferative activity in a large panel of lymphoma-derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l...
June 27, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28648518/selective-inhibition-of-bet-proteins-reduces-pancreatic-damage-and-systemic-inflammation-in-bile-acid-and-fatty-acid-ethyl-ester-but-not-caerulein-induced-acute-pancreatitis-in-mice
#14
Wei Huang, Andrea C Haynes, Rajarshi Mukherjee, Li Wen, Diane Latawiec, Alexei V Tepikin, David N Criddle, Rab K Prinjha, Nicholas Smithers, Robert Sutton
OBJECTIVES: To evaluate the therapeutic potential of I-BET-762, an inhibitor of the bromodomain and extra-terminal (BET) protein family, in experimental acute pancreatitis (AP). METHODS: AP was induced in mice by retrograde infusion of taurolithocholic acid sulphate into the biliopancreatic duct (TLCS-AP) or two intraperitoneal (i.p.) injections of ethanol and palmitoleic acid 1 h apart (FAEE-AP) or 12 hourly i.p. injections of caerulein (CER-AP). In all treatment groups, I-BET-762 (30 mg/kg, i...
June 10, 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
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
#15
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/28636361/machine-learning-assisted-approach-for-discovering-novel-inhibitors-targeting-bromodomain-containing-protein-4
#16
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 antiresistance 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...
July 10, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28624801/bromodomain-inhibition-shows-antitumoral-activity-in-mice-and-human-luminal-breast-cancer
#17
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
#18
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/28619718/click-chemistry-enables-preclinical-evaluation-of-targeted-epigenetic-therapies
#19
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. We modified 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. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments...
June 30, 2017: Science
https://www.readbyqxmd.com/read/28606761/inhibition-of-bromodomain-containing-protein-9-for-the-prevention-of-epigenetically-defined-drug-resistance
#20
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...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
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