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https://www.readbyqxmd.com/read/27904522/inducing-apolipoprotein-a-i-synthesis-to-reduce-cardiovascular-risk-from-assert-to-sustain-and-beyond
#1
Belinda A Di Bartolo, Daniel J Scherer, Stephen J Nicholls
Increasing attention has focused on efforts to promote the biological activities of high-density lipoproteins (HDL) in order to reduce cardiovascular risk. Targeting apolipoprotein A-I (apoA-I), the major protein carried on HDL particles, represents an attractive approach to promoting HDL by virtue of its ability to increase endogenous synthesis of functional HDL particles. A number of pharmacological strategies that target apoA-I, including upregulation of its production with the bromodomain and extraterminal (BET) protein inhibitor RVX-208, development of short peptide sequences that mimic its action, and administration as a component of reconstituted HDL particles, have undergone clinical development...
December 1, 2016: Archives of Medical Science: AMS
https://www.readbyqxmd.com/read/27903752/hexim1-as-a-robust-pharmacodynamic-marker-for-monitoring-target-engagement-of-bet-family-bromodomain-inhibitors-in-tumors-and-surrogate-tissues
#2
Xiaoyu Lin, Xiaoli Huang, Tamar Uziel, Paul Hessler, Daniel H Albert, Lisa A Roberts-Rapp, Keith F McDaniel, Warren M Kati, Yu Shen
An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET bromodomain inhibitor OTX015 using literature-described putative pharmacodynamic (PD) markers such as c-Myc, BRD2, etc. failed to detect PD marker responses in AML patients treated at active dose and those with clinical responses. Here we report the identification and characterization of HEXIM1 and other genes as robust PD markers for BET inhibitors...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#3
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27900832/bromodomain-and-extraterminal-protein-inhibitors-in-pediatrics-a-review-of-the-literature
#4
REVIEW
Irene Jiménez, André Baruchel, François Doz, Johannes Schulte
The last few years have seen the identification of pharmacologic approaches to target bromodomain and extraterminal (BET) proteins for cancer treatment. These proteins have an essential role in gene transcription regulation by binding acetylated lysine residues on histone tails, activating gene transcription. BET inhibitors have been tested in preclinical models including pediatric malignancies and several adult clinical trials are ongoing. Since the development of new drugs in pediatric cancer has long lagged behind programs for adults, the aim of this review is to show the importance of these therapies in pediatric malignancies to support their development in pediatric oncology/hematology...
November 30, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27890933/preclinical-activity-of-cpi-0610-a-novel-small-molecule-bromodomain-and-extra-terminal-protein-inhibitor-in-the-therapy-of-multiple-myeloma
#5
K T Siu, J Ramachandran, A J Yee, H Eda, L Santo, C Panaroni, J A Mertz, R J Sims, M R Cooper, N Raje
Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the anti-tumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing Phase I clinical testing, in multiple myeloma (MM)...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27864418/ampk-ulk1-mediated-autophagy-confers-resistance-to-bet-inhibitor-jq1-in-acute-myeloid-leukemia-stem-cells
#6
Ji Eun Jang, Ju In Eom, Hoi Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
PURPOSE: 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. EXPERIMENTAL DESIGN: We evaluated the levels of apoptosis and 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...
November 18, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27862999/assessment-of-bromodomain-target-engagement-by-a-series-of-bi2536-analogues-with-miniaturized-bet-bret
#7
Luke W Koblan, Dennis L Buckley, Christopher J Ott, Mark E Fitzgerald, Stuart W J Ember, Jin-Yi Zhu, Shuai Liu, Justin M Roberts, David Remillard, Sarah Vittori, Wei Zhang, Ernst Schonbrunn, James E Bradner
Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536...
November 15, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27862857/casticin-induced-apoptotic-cell-death-and-altered-associated-gene-expression-in-human-colon-cancer-colo-205-cells
#8
Hung-Sheng Shang, Jia-You Liu, Hsu-Feng Lu, Han-Sun Chiang, Chia-Hain Lin, Ann Chen, Yuh-Feng Lin, Jing-Gung Chung
Casticin, a polymethoxyflavone, derived from natural plant Fructus Viticis exhibits biological activities including anti-cancer characteristics. The anti-cancer and alter gene expression of casticin on human colon cancer cells and the underlying mechanisms were investigated. Flow cytometric assay was used to measure viable cell, cell cycle and sub-G1 phase, reactive oxygen species (ROS) and Ca(2+) productions, level of mitochondria membrane potential (ΔΨm ) and caspase activity. Western blotting assay was used to detect expression of protein level associated with cell death...
November 14, 2016: Environmental Toxicology
https://www.readbyqxmd.com/read/27858214/synthesis-and-biological-evaluation-of-n-3-oxo-3-4-dihydro-2h-benzo-b-1-4-oxazin-7-yl-benzenesulfonamide-derivatives-as-new-bet-bromodomain-inhibitors-for-anti-hematologic-malignancies-activities
#9
Li Liu, Yongxia Zhu, Zhihao Liu, Tinghong Ye, Weiqiong Zuo, Cuiting Peng, Kunjie Xiao, Ningyu Wang, Luoting Yu
The bromodomain and extra-terminal proteins (BETs), in particular BRD4, has been reported to play important roles in cancer, inflammation, obesity, cardiovascular disease, and neurological disorders. In this paper, a series of benzomorpholinone derivatives were synthesized and biologically evaluated as BETs inhibitors. Detailed structure-activity relationship studies led to the discovery of several new potent compounds, of which 15h and 15i displayed [Formula: see text] values of 2.8 and 4.5 [Formula: see text] against BRD4 (D1), respectively, and showed good anti-proliferation activities against four hematologic malignancies cell lines at low-micromolar concentrations, including MV4-11, OCI-LY10, Pfeifer, and Su-DHL-6 cells...
November 17, 2016: Molecular Diversity
https://www.readbyqxmd.com/read/27835869/otx015-mk-8628-a-novel-bet-inhibitor-exhibits-antitumor-activity-in-non-small-cell-and-small-cell-lung-cancer-models-harboring-different-oncogenic-mutations
#10
Maria E Riveiro, Lucile Astorgues-Xerri, Ramiro Vazquez, Roberta Frapolli, Ivo Kwee, Andrea Rinaldi, Elodie Odore, Keyvan Rezai, Mohamed Bekradda, Giorgio Inghirami, Maurizio D'Incalci, Kay Noel, Esteban Cvitkovic, Eric Raymond, Francesco Bertoni
Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#11
REVIEW
Yasushi Taniguchi
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code...
November 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27821592/bromodomain-and-extra-terminal-proteins-bet-inhibitors-suppress-chondrocyte-differentiation-and-restrain-bone-growth
#12
Ningning Niu, Rui Shao, Guang Yan, Weiguo Zou
Small-molecule inhibitors for bromodomain and extra-terminal proteins (BET) have recently emerged as potential therapeutic agents in clinical trials for various cancers. However, to date, it is unknown whether these inhibitors have side effects on bone structures. Here, we report that inhibition of BET bromodomain proteins may suppress chondrocyte differentiation and restrain bone growth. We generated a luciferase reporter system using the chondrogenic cell line, ATDC5, in which the luciferase gene was driven by the promoter of Col2a1, an elementary collagen of chondrocyte...
November 7, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27809856/t-cells-in-multiple-myeloma-display-features-of-exhaustion-and-senescence-at-the-tumor-site
#13
Claudia Zelle-Rieser, Shanmugapriya Thangavadivel, Rainer Biedermann, Andrea Brunner, Patrizia Stoitzner, Ella Willenbacher, Richard Greil, Karin Jöhrer
BACKGROUND: Multiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments...
November 3, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27809352/t-bet-mediated-tim-3-expression-dampens-monocyte-function-during-chronic-hepatitis-c-virus-infection
#14
Wenjing Yi, Peixin Zhang, Yan Liang, Yun Zhou, Huanjun Shen, Chao Fan, Jonathan P Moorman, Zhi Q Yao, Zhansheng Jia, Ying Zhang
Hepatitis C virus (HCV) induces a high rate of chronic infection via dysregulation of host immunity. We have previously shown that T-cell immunoglobulin and mucin domain protein-3 (Tim-3) is up-regulated on monocyte/macrophages (M/MФ ) during chronic HCV infection; little is known, however, about the transcription factor that controls its expression in these cells. In this study, we investigated the transcription factor, T-box expressed in T cells (T-bet), on Tim-3 expression in M/MФ in the setting of HCV infection...
November 3, 2016: Immunology
https://www.readbyqxmd.com/read/27806195/development-of-new-positron-emission-tomography-radiotracer-for-bet-imaging
#15
Changning Wang, Frederick A Schroeder, Jacob M Hooker
The bromodomain and extra-terminal domain (BET) inhibitors have been extensively studied for tumor treatment in the past few years. Recently, BET-containing proteins have been reported to play a key role in brain functions, such as learning and memory. BET proteins have also been shown to be a potential therapeutic target for substance abuse disorders. Development of a molecular probe for non-invasive imaging will elucidate the distribution and functional roles of BET in the living subject and accelerate medical research and drug discovery in this domain...
November 2, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27803105/bet-inhibitors-suppress-aldh-activity-by-targeting-aldh1a1-super-enhancer-in-ovarian-cancer
#16
Yuhki Yokoyama, Hengrui Zhu, Jeong Heon Lee, Andrew V Kossenkov, Sherry Y Wu, Jayamanna M Wickramasinghe, Xiangfan Yin, Katherine C Palozola, Alessandro Gardini, Louise C Showe, Kenneth S Zaret, Qin Liu, David Speicher, Jose R Conejo-Garcia, James E Bradner, Zhiguo Zhang, Anil K Sood, Tamas Ordog, Benjamin G Bitler, Rugang Zhang
The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27798149/menin-plays-a-critical-role-in-the-regulation-of-the-antigen-specific-cd8-t-cell-response-upon-listeria-infection
#17
Takeshi Yamada, Makoto Kanoh, Shogo Nabe, Toshiaki Yasuoka, Junpei Suzuki, Akira Matsumoto, Makoto Kuwahara, Saho Maruyama, Takuya Fujimoto, Ryo Sakisuka, Masaki Yasukawa, Masakatsu Yamashita
Menin, a tumor suppressor protein, is encoded by the MEN1 gene in humans. Certain germinal mutations of MEN1 induce an autosomal-dominant syndrome that is characterized by concurrent parathyroid adenomas and several other tumor types. Although menin is also expressed in hematopoietic lineages, its role in CD8(+) T cells remains unclear. We generated Menin(flox/flox) CD4-Cre (Menin-KO) mice by crossing Menin(flox/flox) mice with CD4-Cre transgenic (Tg) mice to determine the role of menin in CD8(+) T cells. Wild-type (WT) and Menin-KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8(+) T cells...
October 19, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27775716/potent-and-selective-bivalent-inhibitors-of-bet-bromodomains
#18
Michael J Waring, Huawei Chen, Alfred A Rabow, Graeme Walker, Romel Bobby, Scott Boiko, Rob H Bradbury, Rowena Callis, Edwin Clark, Ian Dale, Danette L Daniels, Austin Dulak, Liz Flavell, Geoff Holdgate, Thomas A Jowitt, Alexey Kikhney, Mark McAlister, Jacqui Méndez, Derek Ogg, Joe Patel, Philip Petteruti, Graeme R Robb, Matthew B Robers, Sakina Saif, Natalie Stratton, Dmitri I Svergun, Wenxian Wang, David Whittaker, David M Wilson, Yi Yao
Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments...
October 24, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27775715/design-and-characterization-of-bivalent-bet-inhibitors
#19
Minoru Tanaka, Justin M Roberts, Hyuk-Soo Seo, Amanda Souza, Joshiawa Paulk, Thomas G Scott, Stephen L DeAngelo, Sirano Dhe-Paganon, James E Bradner
Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors...
December 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27774624/bet-bromodomain-suppression-inhibits-vascular-inflammation-by-blocking-nf-%C3%AE%C2%BAb-and-mapk-activation
#20
Mingcheng Huang, Shan Zeng, Yaoyao Zou, Maohua Shi, Qian Qiu, Youjun Xiao, Guoqiang Chen, Xiuyan Yang, Liuqin Liang, Hanshi Xu
BACKGROUND AND PURPOSE: Increasing evidence indicates the critical role of bromodomain and extra-terminal domain (BET) proteins in regulating immune and inflammatory responses, however, their contribution to vascular inflammation remains to be defined. In this study, we investigated the effect of BET bromodomain inhibition on regulating vascular inflammation and the underlying mechanisms. EXPERIMENTAL APPROACH: Human umbilical vein endothelial cells (HUVECs) were isolated from fresh umbilical cords...
October 24, 2016: British Journal of Pharmacology
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