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Bromodomain inhibitors

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https://www.readbyqxmd.com/read/28215221/targeting-chromatin-remodeling-in-inflammation-and-fibrosis
#1
J Yang, B Tian, A R Brasier
Mucosal surfaces of the human body are lined by a contiguous epithelial cell surface that forms a barrier to aerosolized pathogens. Specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host responses by triggering activation of the nuclear factor κB (NFκB)/RelA transcription factor and formation of a complex with the positive transcription elongation factor (P-TEFb)/cyclin-dependent kinase (CDK)9 and Bromodomain-containing protein 4 (BRD4) epigenetic reader...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28213432/targeting-cancer-cells-with-bet-bromodomain-inhibitors
#2
Yali Xu, Christopher R Vakoc
Cancer cells are often hypersensitive to the targeting of transcriptional regulators, which may reflect the deregulated gene expression programs that underlie malignant transformation. One of the most prominent transcriptional vulnerabilities in human cancer to emerge in recent years is the bromodomain and extraterminal (BET) family of proteins, which are coactivators that link acetylated transcription factors and histones to the activation of RNA polymerase II. Despite unclear mechanisms underlying the gene specificity of BET protein function, small molecules targeting these regulators preferentially suppress the transcription of cancer-promoting genes...
February 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28209615/targeted-degradation-of-bet-proteins-in-triple-negative-breast-cancer
#3
Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer L Meagher, Jeanne Stuckey, Daniel F Hayes, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28207202/the-polar-warhead-of-a-trim24-bromodomain-inhibitor-rearranges-a-water-mediated-interaction-network
#4
Jiuyang Liu, Fudong Li, Hongyu Bao, Yiyang Jiang, Shuya Zhang, Rongsheng Ma, Jia Gao, Jihui Wu, Ke Ruan
Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors...
February 16, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28195723/drug-discovery-targeting-bromodomain-containing-protein-4-brd4
#5
Zhiqing Liu, Pingyuan Wang, Haiying Chen, Eric A Wold, Bing Tian, Allan R Brasier, Jia Zhou
BRD4, the most extensively studied member of BET family, is an epigenetic regulator that localizes to DNA via binding acetylated histones and controls the expression of therapeutically important gene regulatory networks through recruiting transcription factors to form mediator complexes, phosphorylating RNA polymerase II and by its intrinsic histone acetyltransferase activity. Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, etc...
February 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28194432/bet-inhibitors-block-pancreatic-stellate-cell-collagen-i-production-and-attenuate-fibrosis-in-vivo
#6
Krishan Kumar, Brian T DeCant, Paul J Grippo, Rosa F Hwang, David J Bentrem, Kazumi Ebine, Hidayatullah G Munshi
The fibrotic reaction, which can account for over 70%-80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28182006/coordinate-activities-of-brd4-and-cdk9-in-the-transcriptional-elongation-complex-are-required-for-tgf%C3%AE-induced-nox4-expression-and-myofibroblast-transdifferentiation
#7
Talha Ijaz, Mohammad Jamaluddin, Yingxin Zhao, Yueqing Zhang, Jayson Jay, Celeste C Finnerty, David N Herndon, Ronald G Tilton, Allan R Brasier
Transdifferentiation of quiescent dermal fibroblasts to secretory myofibroblasts has a central role in wound healing and pathological scar formation. This myofibroblast transdifferentiation process involves TGFβ-induced de novo synthesis of alpha smooth muscle cell actin (αSMA)+ fibers that enhance contractility as well as increased expression of extracellular matrix (ECM) proteins, including collagen and fibronectin. These processes are mediated upstream by the reactive oxygen species (ROS)-producing enzyme Nox4, whose induction by TGFβ is incompletely understood...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28173625/bet-proteins-an-approach-to-future-therapies-in-transplantation
#8
Beatriz Suarez-Álvarez, Ramón M Rodríguez, Marta Ruiz-Ortega, Carlos López-Larrea
In order to develop new efficient therapies for organ transplantation it is essential to acquire a comprehensive knowledge of the molecular mechanisms and processes, such as immune activation, chronic inflammation and fibrosis that lead to rejection and long-term graft loss. Recent efforts have shed some light on the epigenetic regulation associated with these processes. In this context, the bromo and extraterminal (BET) family of bromodomain proteins (BRD2, BRD3, BRD4 and BRDT) have emerged as major epigenetic players, connecting chromatin structure with gene expression changes...
February 7, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28168222/tgprelid-a-mitochondrial-protein-linked-to-multidrug-resistance-in-the-parasite-toxoplasma-gondii
#9
Victoria Jeffers, Edwin T Kamau, Ananth R Srinivasan, Jonathan Harper, Preethi Sankaran, Sarah E Post, Joseph M Varberg, William J Sullivan, Jon P Boyle
New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite's replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the "reader" module of acetylated lysines...
January 2017: MSphere
https://www.readbyqxmd.com/read/28154167/in-vivo-knockdown-of-pathogenic-proteins-via-specific-and-nongenetic-iap-dependent-protein-erasers-snipers
#10
Nobumichi Ohoka, Keiichiro Okuhira, Masahiro Ito, Katsunori Nagai, Norihito Shibata, Takayuki Hattori, Osamu Ujikawa, Kenichiro Shimokawa, Osamu Sano, Ryokichi Koyama, Hisashi Fujita, Mika Teratani, Hirokazu Matsumoto, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
Many diseases, especially cancers, result from aberrant or over-expression of pathogenic proteins. Specific inhibitors against these proteins have shown remarkable therapeutic effects, but are limited mainly to enzymes. An alternative approach that may have utility in drug development relies on selective degradation of pathogenic proteins via small, chimeric molecules linking an E3 ubiquitin ligase to the targeted protein for proteasomal degradation. To this end, we recently developed a protein-knockdown system based on hybrid small-molecule SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers) that recruit inhibitor of apoptosis protein (IAP) ubiquitin ligases to specifically degrade targeted proteins...
February 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28143717/the-bet-bromodomain-inhibitor-jq1-radiosensitizes-non-small-cell-lung-cancer-cells-by-upregulating-p21
#11
Jian Wang, Ye Wang, Hong Mei, Zhongyuan Yin, Yuanyuan Geng, Tao Zhang, Gang Wu, Zhenyu Lin
Radiotherapy is an important treatment modality in the management of locally advanced non-small cell lung cancer (NSCLC). However, radioresistance markedly impairs its efficacy in clinic. Bromodomain and extra-terminal (BET) bromodomain inhibitors have demonstrated dramatic antitumor activity in several preclinical human cancer models. In this study, we investigated for the first time the effect of JQ1, a novel BET bromodomain inhibitor, on tumor cell radiosensitivity of NSCLC in vitro and in vivo. Our results demonstrated that JQ1 significantly enhanced the effect of irradiation in NSCLC cell lines through a c-myc-independent mechanism...
January 29, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28132895/cbp-p300-bromodomain-mediates-amyloid-formation
#12
Daiqing Liao
Bromodomains are protein domains that serve as "readers" of acetylated lysine marks and mediate DNA-templated processes. In this issue of Cell Chemical Biology, Olzscha et al. (2017) report that the CBP/p300 bromodomains mediate the formation of amyloid-like aggregates and that inhibitors specific to these bromodomains reduce the degree of protein aggregation and mitigate HDAC inhibitor-induced cytotoxicity.
January 26, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28132772/profiling-of-human-epigenetic-regulators-using-a-semi-automated-real-time-qpcr-platform-validated-by-next-generation-sequencing
#13
Amel Dudakovic, Martina Gluscevic, Christopher R Paradise, Halil Dudakovic, Farzaneh Khani, Roman Thaler, Farah S Ahmed, Xiaodong Li, Allan B Dietz, Gary S Stein, Martin A Montecino, David R Deyle, Jennifer J Westendorf, Andre J van Wijnen
Epigenetic mechanisms control phenotypic commitment of mesenchymal stromal/stem cells (MSCs) into osteogenic, chondrogenic or adipogenic lineages. To investigate enzymes and chromatin binding proteins controlling the epigenome, we developed a hybrid expression screening strategy that combines semi-automated real-time qPCR (RT-qPCR), next generation RNA sequencing (RNA-seq), and a novel data management application (FileMerge). This strategy was used to interrogate expression of a large cohort (n>300) of human epigenetic regulators (EpiRegs) that generate, interpret and/or edit the histone code...
April 20, 2017: Gene
https://www.readbyqxmd.com/read/28118076/targeting-ampk-ulk1-mediated-autophagy-for-combating-bet-inhibitor-resistance-in-acute-myeloid-leukemia-stem-cells
#14
Ji Eun Jang, Ju-In Eom, Hoi-Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. We evaluated the levels of apoptosis and macroautophagy/autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+) CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations...
January 24, 2017: Autophagy
https://www.readbyqxmd.com/read/28115161/cg13250-a-novel-bromodomain-inhibitor-suppresses-proliferation-of-multiple-myeloma-cells-in-an-orthotopic-mouse-model
#15
Natsuki Imayoshi, Makoto Yoshioka, Jay Chauhan, Susumu Nakata, Yuki Toda, Steven Fletcher, Jeffrey W Strovel, Kazuyuki Takata, Eishi Ashihara
Multiple myeloma (MM) is characterized by the clonal proliferation of neoplastic plasma cells. Despite a stream of new molecular targets based on better understanding of the disease, MM remains incurable. Epigenomic abnormalities contribute to the pathogenesis of MM. bromodomain 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, binds to acetylated histones during M/G1 transition in the cell cycle promoting progression to S phase. In this study, we investigated the effects of a novel BET inhibitor CG13250 on MM cells...
January 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28114951/hiv-signaling-through-cd4-and-ccr5-activates-rho-family-gtpases-that-are-required-for-optimal-infection-of-primary-cd4-t-cells
#16
Mark B Lucera, Zach Fleissner, Caroline O Tabler, Daniela M Schlatzer, Zach Troyer, John C Tilton
BACKGROUND: HIV-1 hijacks host cell machinery to ensure successful replication, including cytoskeletal components for intracellular trafficking, nucleoproteins for pre-integration complex import, and the ESCRT pathway for assembly and budding. It is widely appreciated that cellular post-translational modifications (PTMs) regulate protein activity within cells; however, little is known about how PTMs influence HIV replication. Previously, we reported that blocking deacetylation of tubulin using histone deacetylase inhibitors promoted the kinetics and efficiency of early post-entry viral events...
January 24, 2017: Retrovirology
https://www.readbyqxmd.com/read/28108460/enhancer-remodeling-during-adaptive-bypass-to-mek-inhibition-is-attenuated-by-pharmacological-targeting-of-the-p-tefb-complex
#17
Jon S Zawistowski, Samantha M Bevill, Daniel R Goulet, Timothy J Stuhlmiller, Adriana S Beltran, Jose F Olivares-Quintero, Darshan Singh, Noah Sciaky, Joel S Parker, Naim U Rashid, Xin Chen, James S Duncan, Martin C Whittle, Steven P Angus, Sara Hanna Velarde, Brian T Golitz, Xiaping He, Charlene Santos, David B Darr, Kristalyn Gallagher, Lee M Graves, Charles M Perou, Lisa A Carey, H Shelton Earp, Gary L Johnson
Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment...
January 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28107481/bet-inhibitors-disrupt-rad21-dependent-conformational-control-of-kshv-latency
#18
Horng-Shen Chen, Alessandra De Leo, Zhuo Wang, Andrew Kerekovic, Robert Hills, Paul M Lieberman
Kaposi's Sarcoma-associated Herpesvirus (KSHV) establishes stable latent infection in B-lymphocytes and pleural effusion lymphomas (PELs). During latency, the viral genome persists as an epigenetically constrained episome with restricted gene expression programs. To identify epigenetic regulators of KSHV latency, we screened a focused small molecule library containing known inhibitors of epigenetic factors. We identified JQ1, a Bromodomain and Extended Terminal (BET) protein inhibitor, as a potent activator of KSHV lytic reactivation from B-cells carrying episomal KSHV...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28103888/photoreceptor-protection-via-blockade-of-bet-epigenetic-readers-in-a-murine-model-of-inherited-retinal-degeneration
#19
Lei Zhao, Jun Li, Yingmei Fu, Mengxue Zhang, Bowen Wang, Jonathan Ouellette, Pawan K Shahi, Bikash R Pattnaik, Jyoti J Watters, Wai T Wong, Lian-Wang Guo
BACKGROUND: The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, and BET4) "read" (bind) histone acetylation marks via two distinct bromodomains (Brom1 and Brom2) facilitating transcriptional activation. These epigenetic "readers" play crucial roles in pathogenic processes such as inflammation. The role of BETs in influencing the degenerative process in the retina is however unknown. METHODS: We employed the rd10 mouse model (Pde6b (rd10) mutation) of retinitis pigmentosa (RP) to examine the involvement of BET proteins in retinal neurodegeneration...
January 19, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28100400/replication-study-bet-bromodomain-inhibition-as-a-therapeutic-strategy-to-target-c-myc
#20
Fraser Aird, Irawati Kandela, Christine Mantis
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al...
January 19, 2017: ELife
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