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Bromodomain inhibitors

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https://www.readbyqxmd.com/read/29139214/a-theoretical-insight-into-selectivity-of-inhibitors-toward-two-domains-of-bromodomain-containing-protein-4-using-molecular-dynamics-simulations
#1
Jing Su, Xinguo Liu, Shaolong Zhang, Fangfang Yan, Qinggang Zhang, Jianzhong Chen
Bromodomains (BRDs) have been an attractive candidate for development of efficient inhibitors toward gene transcription. Molecular dynamics (MD) simulations followed by principal component (PC) analysis were performed to investigate binding selectivity of inhibitors RVX297, BSP, JQ1, SF2523 and CPD2 toward two domains (BD1 and BD2) of bromodomain-containing protein 4 (BRD4). The results show that inhibitor bindings exert different effect on motions of the BC-loops in BD1 and BD2. The rank of binding free energies calculated by using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method agrees with the one determined by experiment...
November 15, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29136404/galectin-3-expression-is-prognostic-in-diffuse-type-gastric-adenocarcinoma-confers-aggressive-phenotype-and-can-be-targeted-by-yap1-bet-inhibitors
#2
Jaffer A Ajani, Jeannelyn S Estrella, Qiongrong Chen, Arlene M Correa, Lang Ma, Ailing W Scott, Jiankang Jin, Bin Liu, Min Xie, Kazuki Sudo, Hironori Shiozaki, Brian Badgwell, Brian Weston, Jeffrey H Lee, Manoop S Bhutani, Hisashi Onodera, Koyu Suzuki, Akihiro Suzuki, Sheng Ding, Wayne L Hofstetter, Randy L Johnson, Robert S Bresalier, Shumei Song
BACKGROUND: Overexpression of Galectin-3 (Gal-3), a β-galactoside binding protein, has been noted in many tumour types but its functional significance and clinical utility in gastric adenocarcinoma (GAC) are not well known. METHODS: We studied 184 GAC patients characterised by histologic grade, sub-phenotypes (diffuse vs intestinal), and ethnicity (Asians vs North Americans). Immunohistochemistry was performed to assess the expression of Gal-3 in human GACs and we correlated it to the clinical outcomes...
November 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29133788/regulation-of-angiotensin-ii-actions-by-enhancers-and-super-enhancers-in-vascular-smooth-muscle-cells
#3
Sadhan Das, Parijat Senapati, Zhuo Chen, Marpadga A Reddy, Rituparna Ganguly, Linda Lanting, Varun Mandi, Anita Bansal, Amy Leung, Selena Zhang, Ye Jia, Xiwei Wu, Dustin E Schones, Rama Natarajan
Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29133261/dual-inhibition-of-brd4-and-pi3k-by-sf2523-suppresses-human-prostate-cancer-cell-growth-in-vitro-and-in-vivo
#4
Gang Shen, Minjun Jiang, Jinxian Pu
Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non-cytotoxic to the prostate epithelial cells...
November 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29113963/gain-of-function-of-asxl1-truncating-protein-in-the-pathogenesis-of-myeloid-malignancies
#5
Hui Yang, Stefan Kurtenbach, Ying Guo, Ines Lohse, Michael A Durante, Jianping Li, Zhaomin Li, Hassan Al-Ali, Lingxiao Li, Zizhen Chen, Matthew G Field, Peng Zhang, Shi Chen, Shohei Yamamoto, Zhuo Li, Yuan Zhou, Stephen D Nimer, J William Harbour, Claes Wahlestedt, Mingjiang Xu, Feng-Chun Yang
Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter driven Flag-Asxl1(Y588X) transgenic mouse model, Asxl1(Y588X) Tg, to express a truncated FLAG-ASXL1(aa1-587) protein in the hematopoietic system. The Asxl1(Y588X) Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations...
November 7, 2017: Blood
https://www.readbyqxmd.com/read/29108467/spop-mediated-degradation-of-brd4-dictates-cellular-sensitivity-to-bet-inhibitors
#6
Xiangpeng Dai, Zhiwei Wang, Wenyi Wei
Bromodomain and extra-terminal (BET) proteins are frequently overexpressed in various human cancers, therefore have been clinically pursed as attractive therapeutic anti-cancer targets. However, relatively little is known about the mechanism(s) underlying aberrant BET overexpression in human cancers. Recently, we reported that prostate cancer-derived SPOP mutants fail to interact with and promote BRD4 degradation, leading to accumulation of BRD4 in prostate cancer cells. As a result, prostate cancer cells harboring SPOP mutations are more resistant to BET inhibitors...
November 6, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29103140/synthesis-and-biological-evaluation-of-indazole-4-7-dione-derivatives-as-novel-brd4-inhibitors
#7
Minjin Yoo, Miyoun Yoo, Ji Eun Kim, Heung Kyoung Lee, Chong Ock Lee, Chi Hoon Park, Kwan-Young Jung
Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide...
November 4, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29082287/flow-cytometric-analysis-of-hiv-1-transcriptional-activity-in-response-to-shrna-knockdown-in-a2-and-a72-j-lat-cell-lines
#8
Daniela Boehm, Melanie Ott
The main obstacle to eradicating HIV-1 from patients is post-integration latency (Finzi et al., 1999). Antiretroviral treatments target only actively replicating virus, while latent infections that have low or no transcriptional activity remain untreated (Sedaghat et al., 2007). To eliminate viral reservoirs, one strategy focuses on reversing HIV-1 latency via 'shock and kill' (Deeks, 2012). The basis of this strategy is to overcome the molecular mechanisms of HIV-1 latency by therapeutically inducing viral gene and protein expression under antiretroviral therapy and to cause selective cell death via the lytic properties of the virus, or the immune system now recognizing the infected cells...
June 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29078358/crispr-cas9-knockouts-reveal-genetic-interaction-between-strain-transcendent-erythrocyte-determinants-of-plasmodium-falciparum-invasion
#9
Usheer Kanjee, Christof Grüring, Mudit Chaand, Kai-Min Lin, Elizabeth Egan, Jale Manzo, Patrick L Jones, Tiffany Yu, Robert Barker, Michael P Weekes, Manoj T Duraisingh
During malaria blood-stage infections, Plasmodium parasites interact with the RBC surface to enable invasion followed by intracellular proliferation. Critical factors involved in invasion have been identified using biochemical and genetic approaches including specific knockdowns of genes of interest from primary CD34(+) hematopoietic stem cells (cRBCs). Here we report the development of a robust in vitro culture system to produce RBCs that allow the generation of gene knockouts via CRISPR/Cas9 using the immortal JK-1 erythroleukemia line...
October 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29077030/dietary-compound-resveratrol-is-a-pan-bet-bromodomain-inhibitor
#10
Luiz Antonio Dutra, David Heidenreich, Gabriel Dalio Bernardes da Silva, Chung Man Chin, Stefan Knapp, Jean Leandro Dos Santos
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2...
October 27, 2017: Nutrients
https://www.readbyqxmd.com/read/29068506/click-chemistry-novel-applications-in-cell-biology-and-drug-discovery
#11
Matthias Gehringer, Stefan A Laufer
A safe BET: Apart from target engagement, subcellular location and tissue distribution are critical parameters in drug discovery. A novel, generalizable approach has been reported that involves exploiting click chemistry to elucidate these parameters. By using clickable analogues of known Bromodomain and extraterminal domain (BET) inhibitors, various labels were introduced in situ and utilized to determine the biological fate of these probes.
October 25, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29067128/i-bet151-inhibits-expression-of-rankl-opg-mmp3-and-mmp9-in-ankylosing-spondylitis-in-vivo-and-in-vitro
#12
Jianping Fan, Jian Zhao, Jie Shao, Xianzhao Wei, Xiaodong Zhu, Ming Li
Ankylosing spondylitis (AS) is characterized by osteoclastogenesis and inflammatory bone resorption. The present study aimed to investigate the effect of bromodomain and extra-terminal domain (BET) protein inhibitor I-BET151 on AS process. A total of 38 AS Chinese patients were recruited and a further 38 sex- and age-matched healthy participants were selected as control. The Bath AS Function Index and Bath AS Disease Activity Index were assessed in AS patients and levels of erythrocyte sedimentation rate and C-reactive protein were measured in AS and healthy groups...
November 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29050985/bromodomain-protein-brd4-promotes-cell-proliferation-in-skin-squamous-cell-carcinoma
#13
Tie Xiang, Jin-Yu Bai, Chang She, Dao-Jiang Yu, Xiao-Zhong Zhou, Tian-Lan Zhao
The present study examined the expression and biological functions of bromodomain-containing protein 4 (BRD4) in skin squamous cell carcinoma (SCC) cells. Our results show that BRD4 mRNA and protein expression was upregulated in human skin SCC cells, as compared to its level in the normal skin keratinocytes and fibroblasts. Treatment with BRD4 inhibitors, JQ1 and CPI203, resulted in proliferation inhibition, apoptosis and cell cycle arrest in both established (A431 cell line) and primary skin SCC cells. Furthermore, BRD4 knockdown (by targeted shRNAs) or knockout (by CRISPR/Cas9) largely inhibited A431 cell proliferation...
October 16, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29050361/bet-inhibitors-as-novel-therapeutic-agents-in-breast-cancer
#14
REVIEW
Alberto Ocaña, Cristina Nieto-Jiménez, Atanasio Pandiella
Tumoral cells not only depend on oncogenic abnormalities to maintain its malignant phenotype but on non-oncogenic vulnerabilities. Targeting epigenomics can modify specific cellular functions required for malignant transformation. The Bromodomain (BRD) family mediates their effect by recruiting proteins of the transcription machinery, recognizing acetylated-lysine residues in nucleosomal histones. Bromodomain and extra-terminal (BET) inhibitors have shown to produce growth inhibition in several tumors through the inhibition of the expression of several transcription factors...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29043777/isoform-selective-atad2-chemical-probe-with-novel-chemical-structure-and-unusual-mode-of-action
#15
Amaury E Fernández-Montalván, Markus Berger, Benno Kuropka, Seong Joo Koo, Volker Badock, Joerg Weiske, Vera Puetter, Simon J Holton, Detlef Stöckigt, Antonius Ter Laak, Paolo A Centrella, Matthew A Clark, Christoph E Dumelin, Eric A Sigel, Holly H Soutter, Dawn M Troast, Ying Zhang, John W Cuozzo, Anthony D Keefe, Didier Roche, Vincent Rodeschini, Apirat Chaikuad, Laura Díaz-Sáez, James M Bennett, Oleg Fedorov, Kilian V M Huber, Jan Hübner, Hilmar Weinmann, Ingo V Hartung, Mátyás Gorjánácz
ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.
October 24, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29032717/bet-inhibitors-in-metastatic-prostate-cancer-therapeutic-implications-and-rational-drug-combinations
#16
Mark C Markowski, Angelo M De Marzo, Emmanuel S Antonarakis
The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer...
October 27, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29027131/selective-bet-protein-inhibition-with-apabetalone-and-cardiovascular-events-a-pooled-analysis-of-trials-in-patients-with-coronary-artery-disease
#17
Stephen J Nicholls, Kausik K Ray, Jan O Johansson, Alan Gordon, Michael Sweeney, Chris Halliday, Ewelina Kulikowski, Norman Wong, Susan W Kim, Gregory G Schwartz
BACKGROUND: Inhibition of bromodomain and extra-terminal (BET) proteins can modulate lipoprotein and inflammatory factors that mediate atherosclerosis. The impact of the BET inhibitor, apabetalone, on cardiovascular events is unknown. OBJECTIVE: Our objective was to investigate the impact of apabetalone on cardiovascular event rates in a pooled analysis of clinical studies in patients with established coronary artery disease. METHODS: We conducted a pooled analysis of patients (n = 798) with coronary artery disease who participated in clinical trials (ASSERT, ASSURE, SUSTAIN) that evaluated the impact of 3-6 months of treatment with apabetalone on lipid parameters and coronary atherosclerosis...
October 12, 2017: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
https://www.readbyqxmd.com/read/28991225/super-enhancers-define-a-proliferative-pgc-1%C3%AE-expressing-melanoma-subgroup-sensitive-to-bet-inhibition
#18
K A Gelato, L Schöckel, O Klingbeil, T Rückert, R Lesche, J Toedling, E Kalfon, M Héroult, P Lejeune, U Mönning, A E Fernández-Montalván, S Bäurle, S Siegel, B Haendler
Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene...
October 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28983590/i%C3%A2-bet151-inhibits-osteoclastogenesis-via-the-rankl-signaling-pathway-in-raw264-7-macrophages
#19
Jing Cheng, Jifu Zheng, Ninghong Guo, Fuming Zi
Excessive bone resorption mediated by osteoclasts may lead to the risk of various lytic bone diseases. In the present study, the effects of I‑BET151, a bromodomain and extra terminal domain protein inhibitor, on osteoclastogenesis in RAW264.7 cells and the underlying mechanism of this process was investigated. Cells were divided into 6 groups, including the control group, receptor activator of nuclear factor‑κB ligand (RANKL) group and 4 other groups containing RANKL and I‑BET151 at different concentrations...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28981843/runx2-expression-in-thyroid-and-breast-cancer-requires-the-cooperation-of-three-non-redundant-enhancers-under-the-control-of-brd4-and-c-jun
#20
Valentina Sancisi, Gloria Manzotti, Mila Gugnoni, Teresa Rossi, Greta Gandolfi, Giulia Gobbi, Federica Torricelli, Francesca Catellani, Italo Faria do Valle, Daniel Remondini, Gastone Castellani, Moira Ragazzi, Simonetta Piana, Alessia Ciarrocchi
Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping...
September 7, 2017: Nucleic Acids Research
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