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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
#1
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/27898717/gene-based-genome-wide-association-analysis-in-european-and-asian-populations-identified-novel-genes-for-rheumatoid-arthritis
#2
Hong Zhu, Wei Xia, Xing-Bo Mo, Xiang Lin, Ying-Hua Qiu, Neng-Jun Yi, Yong-Hong Zhang, Fei-Yan Deng, Shu-Feng Lei
OBJECTIVE: Rheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations. METHODS: Gene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects)...
2016: PloS One
https://www.readbyqxmd.com/read/27865874/bromodomain-containing-protein-2-induces-insulin-resistance-via-the-mtor-akt-signaling-pathway-and-an-inflammatory-response-in-adipose-tissue
#3
Ruixin Sun, Yi Wu, Weihua Hou, Zujun Sun, Yuxiong Wang, Huanhuan Wei, Wei Mo, Min Yu
Insulin resistance is a major metabolic abnormality in a large majority of patients with type II diabetes. Bromodomain-containing protein 2 (Brd2), a transcriptional co-activator/co-repressor with switch mating type/sucrose non-fermenting (SWI/SNF)-like functions that regulates chromatin, suppresses adipocyte differentiation and regulates pancreatic β-cell biology. However, the effects of Brd2 on insulin resistance remain unknown. Here, overexpression of Brd2 in white adipose tissue of wild-type (WT) mice led to insulin resistance...
November 16, 2016: Cellular Signalling
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
#4
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
#5
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/27783056/metabolic-response-to-xd14-treatment-in-human-breast-cancer-cell-line-mcf-7
#6
Daqiang Pan, Michel Kather, Lucas Willmann, Manuel Schlimpert, Christoph Bauer, Simon Lagies, Karin Schmidtkunz, Steffen U Eisenhardt, Manfred Jung, Stefan Günther, Bernd Kammerer
XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells...
October 24, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27769357/clinical-trials-for-bet-inhibitors-run-ahead-of-the-science
#7
REVIEW
Guillaume Andrieu, Anna C Belkina, Gerald V Denis
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27769353/erythropoiesis-provides-a-brd-s-eye-view-of-bet-protein-function
#8
REVIEW
Aaron J Stonestrom, Sarah C Hsu, Michael T Werner, Gerd A Blobel
Pharmacologic inhibitors of the bromodomain and extra-terminal motif (BET) protein family are in clinical trials for the treatment of hematologic malignancies, yet the functions of individual BET proteins remain largely uncharacterized. We review the molecular roles of BETs in the context of erythropoiesis. Studies in this lineage have provided valuable insights into their mechanisms of action, and helped define the individual and overlapping functions of BET protein family members BRD2, BRD3, and BRD4. These studies have important ramifications for our understanding of the molecular and physiologic roles of BET proteins, and provide a framework for elucidating some of the beneficial and adverse effects of pharmacologic inhibitors...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27769352/phospho-brd4-transcription-plasticity-and-drug-targeting
#9
REVIEW
Cheng-Ming Chiang
BRD4 is an epigenetic regulator and transcription cofactor whose phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. While the bromodomains of BET family proteins, including BRD4, BRD2, BRD3 and BRDT, have been the primary targets of small compounds such as JQ1, I-BET and MS417 that show promising anticancer effects against some hematopoietic cancer and solid tumors, drug resistance upon prolonged treatment necessitates a better understanding of alternative pathways underlying not only the resistance but also persistent BET protein dependence for identifying new targets and effective combination therapy strategies...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27651315/brd4-regulates-breast-cancer-dissemination-through-jagged1-notch1-signaling
#10
Guillaume Andrieu, Anna H Tran, Katherine J Strissel, Gerald V Denis
The bromodomain and extraterminal (BET) proteins are epigenetic "readers" of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear how individual family members participate in cancer progression and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here, we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative breast cancer migration and invasion...
September 20, 2016: Cancer Research
https://www.readbyqxmd.com/read/27591477/bet-bromodomain-inhibition-promotes-neurogenesis-while-inhibiting-gliogenesis-in-neural-progenitor-cells
#11
Jingjun Li, Jing Ma, Guofeng Meng, Hong Lin, Sharon Wu, Jamie Wang, Jie Luo, Xiaohong Xu, David Tough, Matthew Lindon, Inma Rioja Pastor, Jing Zhao, Hongkang Mei, Rab Prinjha, Zhong Zhong
Neural stem cells and progenitor cells (NPCs) are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers...
July 20, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27451123/small-molecule-targeting-of-bet-proteins-in-cancer
#12
C A French
BET proteins have recently become recognized for their role in a broad range of cancers and are defined by the presence of two acetyl-histone reading bromodomains and an ET domain. This family of proteins includes BRD2, BRD3, BRD4, and BRDT. BRD4 is the most-studied BET protein in cancer, and normally serves as an epigenetic reader that links active chromatin marks to transcriptional elongation through activation of RNA polymerase II. The role of BRD3 and BRD4 first became known in cancer as mutant oncoproteins fused to the p300-recruiting NUT protein in a rare aggressive subtype of squamous cell cancer known as NUT midline carcinoma (NMC)...
2016: Advances in Cancer Research
https://www.readbyqxmd.com/read/27388964/otx015-mk-8628-a-novel-bet-inhibitor-displays-in-vitro-and-in-vivo-antitumor-effects-alone-and-in-combination-with-conventional-therapies-in-glioblastoma-models
#13
Caroline Berenguer-Daizé, Lucile Astorgues-Xerri, Elodie Odore, Mylène Cayol, Esteban Cvitkovic, Kay Noel, Mohamed Bekradda, Sarah MacKenzie, Keyvan Rezai, François Lokiec, Maria E Riveiro, L'Houcine Ouafik
Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines...
November 1, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27308593/histone-variant-h2a-z-2-a-novel-driver-of-melanoma-progression
#14
Chiara Vardabasso, Sandra B Hake, Emily Bernstein
Histone variants are attracting attention in the field of cancer epigenetics. Our study has established a novel role for the uncharacterized histone variant H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 promotes cellular proliferation by recruiting BRD2 and E2F1 to E2F target genes and facilitating their transcription. High H2A.Z.2 expression correlates with poor survival in patients, and its depletion sensitizes cells to chemotherapy and targeted therapies.
March 2016: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/27282480/rvx-297-a-novel-bd2-selective-inhibitor-of-bet-bromodomains
#15
Olesya A Kharenko, Emily M Gesner, Reena G Patel, Karen Norek, Andre White, Eric Fontano, Robert K Suto, Peter R Young, Kevin G McLure, Henrik C Hansen
Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles...
August 12, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27243809/a-novel-phenanthridionone-based-scaffold-as-a-potential-inhibitor-of-the-brd2-bromodomain-crystal-structure-of-the-complex
#16
Shailesh Tripathi, Shruti Mathur, Prashant Deshmukh, Ramu Manjula, Balasundaram Padmanabhan
Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET (bromodomain and extra-terminal) family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases...
2016: PloS One
https://www.readbyqxmd.com/read/27169995/regulation-of-gli-underlies-a-role-for-bet-bromodomains-in-pancreatic-cancer-growth-and-the-tumor-microenvironment
#17
Yinshi Huang, Sabikun Nahar, Akifumi Nakagawa, Maite G Fernandez-Barrena, Jennifer A Mertz, Barbara M Bryant, Curtis E Adams, Mari Mino-Kenudson, Kate N Von Alt, Kevin Chang, Andrew R Conery, Charlie Hatton, Robert J Sims, Martin E Fernandez-Zapico, Xingpeng Wang, Keith D Lillemoe, Carlos Fernández-Del Castillo, Andrew L Warshaw, Sarah P Thayer, Andrew S Liss
PURPOSE: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. EXPERIMENTAL DESIGN: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models...
August 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27110299/the-bromodomain-inhibitor-n-methyl-pyrrolidone-reduced-fat-accumulation-in-an-ovariectomized-rat-model
#18
Bebeka Gjoksi, Chafik Ghayor, Indranil Bhattacharya, Marcy Zenobi-Wong, Franz E Weber
BACKGROUND: Weight gain is one of the consequences of estrogen deficiency and constitutes a major health problem. The present study highlights the effects of N-methyl pyrrolidone (NMP) on adipogenesis in osteoporosis induced by estrogen deficiency in an ovariectomized rat model. RESULTS: Ovariectomy resulted in body weight gain, increased femoral marrow adipocytes, and hypertrophic adipocytes in white adipose tissue, distorted serum leptin, and TNF-α and PPARγ levels...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/27078884/nonselective-inhibition-of-the-epigenetic-transcriptional-regulator-bet-induces-marked-lymphoid-and-hematopoietic-toxicity-in-mice
#19
Dong U Lee, Paula Katavolos, Gopinath Palanisamy, Arna Katewa, Charly Sioson, Janice Corpuz, Jodie Pang, Kevin DeMent, Edna Choo, Nico Ghilardi, Dolores Diaz, Dimitry M Danilenko
Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones...
June 1, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27074708/signal-transducer-and-activator-of-transcription-stat5-is-recruited-to-c-myc-super-enhancer
#20
Sophia Pinz, Samy Unser, Anne Rascle
BACKGROUND: c-Myc has been proposed as a putative target gene of signal transducer and activator of transcription 5 (STAT5). No functional STAT5 binding site has been identified so far within the c-Myc gene locus, therefore a direct transcriptional regulation by STAT5 remains uncertain. c-Myc super-enhancer, located 1.7 Mb downstream of the c-Myc gene locus, was recently reported as essential for the regulation of c-Myc gene expression by hematopoietic transcription factors and bromodomain and extra-terminal (BET) proteins and for leukemia maintenance...
2016: BMC Molecular Biology
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