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https://www.readbyqxmd.com/read/29777702/microrna-608-inhibits-human-hepatocellular-carcinoma-cell-proliferation-via-targeting-the-bet-family-protein-brd4
#1
Ling He, Dijuan Meng, Shi-Hu Zhang, Yi Zhang, Zhengming Deng, Lian-Bao Kong
Over-expression of the bromodomain and extraterminal (BET) family protein BRD4 is associated with hepatocellular carcinoma (HCC) progression. In the present study, we indentified a novel putative anti-BRD4 microRNA: microRNA-608 ("miR-608"). In HepG2 cells and primary human HCC cells, over-expression of miR-608, using a lentiviral construct, induced BRD4 downregulation and proliferation inhibition. Conversely, transfection of the miR-608 inhibitor increased BRD4 expression to promote HepG2 cell proliferation...
May 16, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29777682/inhibition-of-bet-bromodomains-restores-corticosteroid-responsiveness-in-a-mixed-granulocytic-mouse-model-of-asthma
#2
Ahmed Nadeem, Sheikh F Ahmad, Naif O Al-Harbi, Nahid Siddiqui, Khalid E Ibrahim, Sabry M Attia
Asthma is a heterogeneous disease characterized by different endotypes/phenotypes. Th2/Th17 driven mixed granulocytic asthma is one of them and shows resistance to corticosteroid therapy. Bromodomain and extra-terminal (BET) proteins are required for differentiation of Th17 cells which play a pivotal role in neutrophilic inflammation. Therefore, we sought to characterize the differential effects of BET inhibitor versus corticosteroids, and their potential synergism in cockroach allergen extract (CE)-induced mixed granulocytic (eosinophilic and neutrophilic) mouse model of asthma having Th2/Th17 endotype...
May 16, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29777137/enhanced-efficacy-of-combined-temozolomide-and-bromodomain-inhibitor-therapy-for-gliomas-using-targeted-nanoparticles
#3
Fred C Lam, Stephen W Morton, Jeffrey Wyckoff, Tu-Lan Vu Han, Mun Kyung Hwang, Amanda Maffa, Elena Balkanska-Sinclair, Michael B Yaffe, Scott R Floyd, Paula T Hammond
Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1...
May 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29776834/bet-bromodomain-ligands-probing-the-wpf-shelf-to-improve-brd4-bromodomain-affinity-and-metabolic-stability
#4
Laura E Jennings, Matthias Schiedel, David S Hewings, Sarah Picaud, Corentine M C Laurin, Paul A Bruno, Joseph P Bluck, Amy R Scorah, Larissa See, Jessica K Reynolds, Mustafa Moroglu, Ishna N Mistry, Amy Hicks, Pavel Guzanov, James Clayton, Charles N G Evans, Giulia Stazi, Philip C Biggin, Anna K Mapp, Ester M Hammond, Philip G Humphreys, Panagis Filippakopoulos, Stuart J Conway
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t½  = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04...
May 15, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29770599/structural-analysis-of-small-molecule-binding-to-the-baz2a-and-baz2b-bromodomains
#5
Andrea Dalle Vedove, Dimitrios Spiliotopoulos, Vito Giuseppe D'Agostino, Jean-Rémy Marchand, Andrea Unzue, Cristina Nevado, Graziano Lolli, Amedeo Caflisch
The bromodomain-containing protein BAZ2A is a validated target in prostate cancer, while the function of its paralog BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a very similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand makes essentially identical interactions in the BAZ2A and BAZ2B bromodomains...
May 17, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29767555/protective-effect-of-the-bet-protein-inhibitor-jq1-in-cisplatin-induced-nephrotoxicity
#6
Liping Sun, Jing Liu, Yanggang Yuan, Xinzhou Zhang, Zheng Dong
As a potent chemotherapy drug, cisplatin is also notorious for its side effects including nephrotoxicity in kidneys, presenting a pressing need to identify renoprotective agents. Cisplatin nephrotoxicity involves epigenetic regulations, including changes in histone acetylation. Bromodomain and extra-terminal (BET) proteins are "readers" of the epigenetic code of histone acetylation. Here, we investigated the potential renoprotective effects of JQ1, a small molecule inhibitor of BET proteins. We show that JQ1 significantly ameliorated cisplatin-induced nephrotoxicity in mice as indicated by the measurements of kidney function, histopathology, and renal tubular apoptosis...
May 16, 2018: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29764999/targetable-bet-proteins-and-e2f1-dependent-transcriptional-program-maintains-the-malignancy-of-glioblastoma
#7
Liang Xu, Ye Chen, Anand Mayakonda, Lynnette Koh, Yuk Kien Chong, Dennis L Buckley, Edwin Sandanaraj, See Wee Lim, Ruby Yu-Tong Lin, Xin-Yu Ke, Mo-Li Huang, Jianxiang Chen, Wendi Sun, Ling-Zhi Wang, Boon Cher Goh, Huy Q Dinh, Dennis Kappei, Georg E Winter, Ling-Wen Ding, Beng Ti Ang, Benjamin P Berman, James E Bradner, Carol Tang, H Phillip Koeffler
Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells...
May 15, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29764852/combined-hdac-and-bromodomain-protein-inhibition-reprograms-tumor-cell-metabolism-and-elicits-synthetic-lethality-in-glioblastoma
#8
Yiru Zhang, Chiaki Tsuge Ishida, Wataru Ishida, Sheng-Fu L Lo, Junfei Zhao, Chang Shu, Elena Bianchetti, Giulio Kleiner, Maria Sanchez-Quintero, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D Siegelin
PURPOSE: Glioblastoma remain a challenge in oncology in part due to tumor heterogeneity. EXPERIMENTAL DESIGN: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems. RESULTS: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that combined histone deacetylase (HDAC) inhibition and Bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells...
May 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29764756/straightforward-hit-identification-approach-in-fragment-based-discovery-of-bromodomain-containing-protein-4-brd4-inhibitors
#9
Petro Borysko, Yurii S Moroz, Oleksandr V Vasylchenko, Vasyl V Hurmach, Anastasia Starodubtseva, Natalia Stefanishena, Kateryna Nesteruk, Sergey Zozulya, Ivan S Kondratov, Oleksandr O Grygorenko
A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total)...
May 9, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29760405/arid1a-mutation-sensitizes-most-ovarian-clear-cell-carcinomas-to-bet-inhibitors
#10
Katrien Berns, Joseph J Caumanns, E Marielle Hijmans, Annemiek M C Gennissen, Tesa M Severson, Bastiaan Evers, G Bea A Wisman, Gert Jan Meersma, Cor Lieftink, Roderick L Beijersbergen, Hiroaki Itamochi, Ate G J van der Zee, Steven de Jong, René Bernards
Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells...
May 15, 2018: Oncogene
https://www.readbyqxmd.com/read/29758518/benzoxazinone-containing-3-5-dimethylisoxazole-derivatives-as-bet-bromodomain-inhibitors-for-treatment-of-castration-resistant-prostate-cancer
#11
Xiaoqian Xue, Yan Zhang, Chao Wang, Maofeng Zhang, Qiuping Xiang, Junjian Wang, Anhui Wang, Chenchang Li, Cheng Zhang, Lingjiao Zou, Rui Wang, Shuang Wu, Yongzhi Lu, Hongwu Chen, Ke Ding, Guohui Li, Yong Xu
The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B...
April 21, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29758466/structural-dynamics-and-quantum-mechanical-aspects-of-shikonin-derivatives-as-crebbp-bromodomain-inhibitors
#12
Sarmistha Mitra, Raju Dash
The Proteins involved in the chemical modification of lysine residues in histone, is currently being excessively focused as the therapeutic target for the treatment of cell related diseases like cancer. Among these proteins, the epigenetic reader, CREB-binding protein (CREBBP) bromodomain is one of the most prominent targets for effective anticancer drug design, which is responsible for the reorganization of acetylated histone lysine residues. Therefore, this study employed an integrative approach of structure based drug design, in combination with Molecular Dynamics (MD) and QM/MM study to identify as well as to describe the binding mechanism of two shikonin derivatives, acetylshikonin and propionylshikonin as inhibitors of CREBBP bromodomain...
May 4, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29755274/nut-carcinoma-of-the-sinonasal-tract-infiltrating-the-orbit-in-a-man-with-birdshot-chorioretinitis
#13
Wesley Chan, Martin J Bullock, Arif F Samad, Curtis W Archibald, J Godfrey Heathcote
A 48-year-old man with a history of birdshot chorioretinitis presented with blurry vision, retro-bulbar pain and sinusitis. Though visual acuity was unaffected, he had left optic disc oedema and mild restriction of left eye abduction. His symptoms progressed quickly, with diplopia in primary gaze, epistaxis from his left nostril, and a left relative afferent pupillary defect (RAPD). On computed tomography, there was a mass in the nasal cavity that extended through the left cribriform plate and lamina papyracea and posteriorly into the optic canal...
January 2018: Saudi Journal of Ophthalmology: Official Journal of the Saudi Ophthalmological Society
https://www.readbyqxmd.com/read/29754817/vitamin-d-switches-baf-complexes-to-protect-%C3%AE-cells
#14
Zong Wei, Eiji Yoshihara, Nanhai He, Nasun Hah, Weiwei Fan, Antonio F M Pinto, Timothy Huddy, Yuhao Wang, Brittany Ross, Gabriela Estepa, Yang Dai, Ning Ding, Mara H Sherman, Sungsoon Fang, Xuan Zhao, Christopher Liddle, Annette R Atkins, Ruth T Yu, Michael Downes, Ronald M Evans
A primary cause of disease progression in type 2 diabetes (T2D) is β cell dysfunction due to inflammatory stress and insulin resistance. However, preventing β cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and β cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to PBAF and BAF chromatin remodeling complexes, respectively...
May 7, 2018: Cell
https://www.readbyqxmd.com/read/29752320/rediagnosis-of-lung-cancer-as-nut-midline-carcinoma-based-on-clues-from-tumor-genomic-profiling
#15
Alexander S Baras, Jarushka Naidoo, Christine L Hann, Peter B Illei, Charles W Reninger, Josh Lauring
Tumor DNA sequencing can identify rare driver genomic alterations that suggest targets for cancer therapy, even when these drivers cannot be suspected on clinical grounds. In some cases, genomic alterations identified in the tumor can lead to a change in diagnosis with implications for prognosis and therapy. This report describes a case in which evaluation of tumor sequencing results by a molecular tumor board (MTB) led to rediagnosis of a non-small cell lung cancer as highly aggressive NUT midline carcinoma, with implications for targeted therapy using an investigational bromodomain and extraterminal (BET) inhibitor...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29751762/hiv-latency-reversing-agents-act-through-tat-post-translational-modifications
#16
Georges Khoury, Talia M Mota, Shuang Li, Carolin Tumpach, Michelle Y Lee, Jonathan Jacobson, Leigh Harty, Jenny L Anderson, Sharon R Lewin, Damian F J Purcell
BACKGROUND: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing...
May 11, 2018: Retrovirology
https://www.readbyqxmd.com/read/29748248/bromodomain-protein-brd4-is-increased-in-human-placentas-from-women-with-early-onset-preeclampsia
#17
Stella Liong, Gillian Barker, Martha Lappas
Preeclampsia affects 5% of all pregnancies and is a serious disorder of pregnancy, characterised by high maternal blood pressure, placental hypoxia, fluid retention (oedema) and proteinuria. Women with preeclampsia are associated with exaggerated levels of pro-inflammatory cytokines, chemokines and anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFLT1). Studies in non-gestational tissues have described the bromodomain (BRD) and extraterminal family of proteins, in particular BRD4 to play a critical role in propagating inflammation and is currently a therapeutic target for treating cancer, lung inflammation and asthma...
June 2018: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/29743242/cyclin-dependent-kinase-7-cdk7-mediated-phosphorylation-of-the-cdk9-activation-loop-promotes-p-tefb-assembly-with-tat-and-proviral-hiv-reactivation
#18
Uri Mbonye, Benlian Wang, Giridharan Gokulrangan, Wuxian Shi, Sichun Yang, Jonathan Karn
The HIV trans-activator Tat recruits the host transcription elongation factor P-TEFb to stimulate proviral transcription. Phosphorylation of Thr186 on the activation loop (T-loop) of cyclin-dependent kinase 9 (CDK9) is essential for its kinase activity and assembly of CDK9 and cyclin T1 (CycT1) to form functional P-TEFb. Phosphorylation of a second highly conserved T-loop site, Ser175, alters the competitive binding of Tat and the host recruitment factor bromodomain containing 4 (BRD4) to P-TEFb. Here, we investigated the intracellular mechanisms that regulate these key phosphorylation events required for HIV transcription...
May 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29733771/phase-ib-trial-with-birabresib-a-small-molecule-inhibitor-of-bromodomain-and-extraterminal-proteins-in-patients-with-selected-advanced-solid-tumors
#19
Jeremy Lewin, Jean-Charles Soria, Anastasios Stathis, Jean-Pierre Delord, Solange Peters, Ahmad Awada, Philippe G Aftimos, Mohamed Bekradda, Keyvan Rezai, Zhen Zeng, Azher Hussain, Susan Perez, Lillian L Siu, Christophe Massard
Purpose Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study. Patients and Methods Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design...
May 7, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29732121/optimization-of-a-bump-and-hole-approach-to-allele-selective-bet-bromodomain-inhibition
#20
A C Runcie, M Zengerle, K-H Chan, A Testa, L van Beurden, M G J Baud, O Epemolu, L C J Ellis, K D Read, V Coulthard, A Brien, A Ciulli
Allele-specific chemical genetics enables selective inhibition within families of highly-conserved proteins. The four BET (bromodomain & extra-terminal domain) proteins - BRD2, BRD3, BRD4 and BRDT bind acetylated chromatin via their bromodomains and regulate processes such as cell proliferation and inflammation. BET bromodomains are of particular interest, as they are attractive therapeutic targets but existing inhibitors are pan-selective. We previously established a bump-&-hole system for the BET bromodomains, pairing a leucine/alanine mutation with an ethyl-derived analogue of an established benzodiazepine scaffold...
March 7, 2018: Chemical Science
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