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Bromodomain

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https://www.readbyqxmd.com/read/29156797/jq1-synergizes-with-the-bcl-2-inhibitor-abt-263-against-mycn-amplified-small-cell-lung-cancer
#1
Huogang Wang, Bo Hong, Xuemin Li, Ke Deng, Hong Li, Vivian Wai Yan Lui, Wenchu Lin
Small cell lung cancer (SCLC) is a clinically aggressive cancer with very poor prognosis. Amplification of MYC family genes and overexpression of Bcl-2 protein are common in SCLC, and they are likely therapeutic targets for SCLC. Previous clinical study showed that single agent targeting Bcl-2 with ABT-263 was of limited efficacy in SCLC. In this study, we demonstrated for the first time that co-targeting of N-Myc and Bcl-2 resulted in marked synergistic antitumor effects in MYCN-amplified SCLC. We found that MYCN-amplified SCLC cells were highly sensitive to a Bromodomain and Extra-Terminal domain (BET) inhibitor JQ1, which was able to inhibit N-Myc protein expression...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156698/combined-brd4-and-cdk9-inhibition-as-a-new-therapeutic-approach-in-malignant-rhabdoid-tumors
#2
Natalia Moreno, Till Holsten, Julius Mertins, Annabelle Zhogbi, Pascal Johann, Marcel Kool, Michael Meisterernst, Kornelius Kerl
Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29155580/a-unique-approach-to-design-potent-and-selective-cyclic-adenosine-monophosphate-response-element-binding-protein-binding-protein-cbp-inhibitors
#3
Sarah M Bronner, Jeremy M Murray, F Anthony Romero, Kwong Wah Lai, Vickie Tsui, Patrick Cyr, Maureen H Beresini, Gladys de Leon Boenig, Zhongguo Chen, Edna F Choo, Kevin R Clark, Terry D Crawford, Hariharan Jayaram, Susan Kaufman, Ruina Li, Yingjie Li, Jiangpeng Liao, Xiaorong Liang, Wenfeng Liu, Justin Q Ly, Jonathan Maher, John S Wai, Fei Wang, Aijun Zheng, Xiaoyu Zhu, Steven R Magnuson
The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we reported the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region, and then building into the LPF shelf. Herein we report the "hybridization" of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To demonstrate the utility of our hybridization approach, two analogues containing unique Asn binders and the optimized tetrahydroquinoline moiety were rapidly optimized to yield single-digit nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1) and the broader bromodomain family...
November 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29154989/targeting-bromodomain-and-extraterminal-proteins-in-breast-cancer
#4
REVIEW
Jennifer M Sahni, Ruth A Keri
Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously...
November 15, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29149598/harnessing-bet-inhibitor-sensitivity-reveals-amigo2-as-a-melanoma-survival-gene
#5
Barbara Fontanals-Cirera, Dan Hasson, Chiara Vardabasso, Raffaella Di Micco, Praveen Agrawal, Asif Chowdhury, Madeleine Gantz, Ana de Pablos-Aragoneses, Ari Morgenstern, Pamela Wu, Dan Filipescu, David Valle-Garcia, Farbod Darvishian, Jae-Seok Roe, Michael A Davies, Christopher R Vakoc, Eva Hernando, Emily Bernstein
Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29148850/atad2-in-cancer-a-pharmacologically-challenging-but-tractable-target
#6
Muzammal Hussain, Yang Zhou, Yu Song, H M Adnan Hameed, Hao Jiang, Yaoquan Tu, Jiancun Zhang
ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a "difficult to drug" or "least druggable" target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding...
November 17, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29142067/jq1-induces-dna-damage-and-apoptosis-and-inhibits-tumor-growth-in-a-patient-derived-xenograft-model-of-cholangiocarcinoma
#7
Patrick L Garcia, Aubrey L Miller, Tracy L Gamblin, Leona N Council, John D Christein, J Pablo Arnoletti, Marty J Heslin, Sushanth Reddy, Joseph H Richardson, Xiangqin Cui, Robert C A M van Waardenburg, James E Bradner, Eddy S Yang, Karina J Yoon
Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA...
November 15, 2017: Molecular Cancer Therapeutics
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
#8
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
#9
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
#10
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
#11
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/29133117/application-of-mixed-peptide-arrays-to-study-combinatorial-readout-of-chromatin-modifications
#12
Rebekka Mauser, Goran Kungulovski, David Meral, Daniel Maisch, Albert Jeltsch
The N-terminal tails of histone proteins are massively decorated with post-translational modifications (PTMs), which play important roles in the regulation of gene expression. Several highly conserved chromatin interacting proteins can bind to histone modifications in a sequence and modification specific manner employing specific reading domains. These proteins often contain several reading domains, which can cooperate in the readout of different PTMs. To gain a better insight into the combinatorial readout of PTMs, we developed a method to study the binding of double reading domains to mixed peptide arrays containing two different peptides in each spot...
November 10, 2017: Biochimie
https://www.readbyqxmd.com/read/29127434/brd7-regulates-the-insulin-signaling-pathway-by-increasing-phosphorylation-of-gsk3%C3%AE
#13
Lena Golick, Youngah Han, Yoo Kim, Sang Won Park
Reduced hepatic expression levels of bromodomain-containing protein 7 (BRD7) have been suggested to play a role in the development of glucose intolerance in obesity. However, the molecular mechanism by which BRD7 regulates glucose metabolism has remained unclear. Here, we show that BRD7 increases phosphorylation of glycogen synthase kinase 3β (GSK3β) in response to activation of the insulin receptor-signaling pathway shortly after insulin stimulation and the nutrient-sensing pathway after feeding. BRD7 mediates phosphorylation of GSK3β at the Serine 9 residue and this effect on GSK3β occurs even in the absence of AKT activity...
November 10, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29121973/in-vitro-investigations-on-extracellular-proteins-secreted-by-aphanomyces-invadans-the-causative-agent-of-epizootic-ulcerative-syndrome
#14
Muhammad Majeed, Gokhlesh Kumar, Sarah Schlosser, Mansour El-Matbouli, Mona Saleh
BACKGROUND: Proteases produced by many microorganisms, including oomycetes, are crucial for their growth and development. They may also play a critical role in disease manifestation. Epizootic ulcerative syndrome is one of the most destructive fish diseases known. It is caused by the oomycete Aphanomyces invadans and leads to mass mortalities of cultured and wild fish in many countries. The areas of concern are Australia, China, Japan, South and Southeast Asian countries and the USA. Extracellular proteases produced by this oomycete are believed to trigger EUS pathogenesis in fish...
November 9, 2017: Acta Veterinaria Scandinavica
https://www.readbyqxmd.com/read/29113963/gain-of-function-of-asxl1-truncating-protein-in-the-pathogenesis-of-myeloid-malignancies
#15
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
#16
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
#17
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
#18
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
#19
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 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29077715/protein-dynamics-and-structural-waters-in-bromodomains
#20
Xiaoxiao Zhang, Kai Chen, Yun-Dong Wu, Olaf Wiest
Bromodomains are epigenetic readers of acetylated lysines that are integral parts of histone tails. The 61 bromodomains in humans are structurally highly conserved but specifically bind to widely varying recognition motifs, suggesting that dynamic rather than static factors are responsible for recognition selectivity. To test this hypothesis, the dynamics of the binding sites and structural water molecules of four bromodomains (ATAD2, BAZ2B, BRD2(1) and CREBBP) representing four different subtypes is studied with 1 μs MD simulations using the RSFF2 force field...
2017: PloS One
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