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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...
October 24, 2016: Nature Chemical Biology
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
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
Fuyumi Kato, Francesco Paolo Fiorentino, Andreu Alibés, Manuel Perucho, Montse Sánchez-Céspedes, Takashi Kohno, Jun Yokota
We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification...
October 14, 2016: Oncotarget
Pei Y Liu, Nicholas Sokolowski, Su T Guo, Faraz Siddiqi, Bernard Atmadibrata, Thomas J Telfer, Yuting Sun, Lihong Zhang, Denise Yu, Joshua Mccarroll, Bing Liu, Rui H Yang, Xiang Y Guo, Andrew E Tee, Ken Itoh, Jenny Wang, Maria Kavallaris, Michelle Haber, Murray D Norris, Belamy B Cheung, Jennifer A Byrne, David S Ziegler, Glenn M Marshall, Marcel E Dinger, Rachel Codd, Xu D Zhang, Tao Liu
BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2...
October 13, 2016: Oncotarget
Ke Ren, Wei Zhang, Xiaoqing Chen, Yingyu Ma, Yue Dai, Yimei Fan, Yayi Hou, Ren Xiang Tan, Erguang Li
The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection...
October 2016: PLoS Pathogens
Haiwei Lian, Dun Li, Yun Zhou, Esther Landesman-Bollag, Guanglan Zhang, Nicole M Anderson, Kevin Charles Tang, Justine E Roderick, Michelle A Kelliher, David C Seldin, Hui Fu, Hui Feng
No abstract text is available yet for this article.
October 6, 2016: Haematologica
Min Huang, Jacqueline S Garcia, Daniel Thomas, Li Zhu, Le Xuan Truong Nguyen, Steven M Chan, Ravindra Majeti, Bruno C Medeiros, Beverly S Mitchell
The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1...
October 6, 2016: Oncotarget
Qiong Duan, Yi Xiao, Lingyan Zhu, Zhenzhen Liu, Xiaoxiao Mao, Zhengxiang Zhou, Chaonan Liao, Jinxing Cai, Fulian Huang, Zehao Liu, Jian Zeng, Ke Xia, Cheng Chang, Jun Qi, Zihua Chen, He Huang, Tianlun Yang
Transcriptional coactivator with PDZ-binding motif (TAZ) is a key transcriptional mediator of Hippo signaling that has been recently reported to mediate Wnt-activated transcription and serve as a component to suppress canonical Wnt/β-catenin activity. The Bromodomain and Extra-terminal domain (BET) family of proteins can recognize the acetylated lysine chain on histones and plays a critical role in transcriptional regulation. However, the mechanisms underlying transcriptional repression by the BET bromodomain are poorly understood...
October 4, 2016: Biochimica et Biophysica Acta
Yufang Ma, Lihong Wang, Leif R Neitzel, Sudan Loganathan, Nan Tang, Lili Qin, Crispi E Emily, Yan Guo, Stefan Knapp, Robert D Beauchamp, Ethan Lee, Jialiang Wang
PURPOSE: The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer (CRC)...
September 27, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
D T Saenz, W Fiskus, T Manshouri, K Rajapakshe, S Krieger, B Sun, C P Mill, C DiNardo, N Pemmaraju, T Kadia, S Parmar, S Sharma, C Coarfa, P Qiu, S Verstovsek, K N Bhalla
Myeloproliferative Neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of JAK-STAT signaling, which responds to treatment with the JAK1 & 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary AML (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extra terminal) protein inhibitor (BETi), e...
September 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Marc Baud'huin, François Lamoureux, Camille Jacques, Lidia Rodriguez Calleja, Thibaut Quillard, Céline Charrier, Jérome Amiaud, Martine Berreur, Bénédicte Brounais-LeRoyer, Robert Owen, Gwendolen C Reilly, James E Bradner, Dominique Heymann, Benjamin Ory
Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro...
September 23, 2016: Bone
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
Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R Rutkowski, Benjamin G Bitler, Michael J Allegrezza, Yuhki Yokoyama, Andrew V Kossenkov, James E Bradner, Jose R Conejo-Garcia, Rugang Zhang
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells...
September 13, 2016: Cell Reports
Aki Yamada, Kazue Honma, Kazuki Mochizuki, Toshinao Goda
OBJECTIVE: Fructose intake induces hepatic steatosis by activating fat synthesis. In this study, we searched for genes that showed acute induction in the livers of mice force-fed with fructose, and examined how this induction is regulated. MATERIALS/METHODS: We identified genes induced at 6h after the fructose force-feeding using a microarray and quantitative real-time RT-PCR. Histone acetylation and an acetylated histone binding protein bromodomain containing (BRD)4 binding around the fructose-inducible genes were examined using a chromatin immunoprecipitation assay...
October 2016: Metabolism: Clinical and Experimental
Olaf Klingbeil, Ralf Lesche, Kathy A Gelato, Bernard Haendler, Pascale Lejeune
Non-small cell lung cancer (NSCLC) has the highest incidence of cancer-related death worldwide and a high medical need for more effective therapies. Small-molecule inhibitors of the bromodomain and extra terminal domain (BET) family such as JQ1, I-BET762 and OTX-015 are active in a wide range of different cancer types, including lung cancer. Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the effects of BET inhibition on the apoptotic pathway remain largely unknown...
2016: Cell Death & Disease
Molly E Church, Marko Estrada, Christian M Leutenegger, Florante N Dela Cruz, Patricia A Pesavento, Kevin Woolard
Polyomavirus infection often results in persistence of the viral genome with little or no virion production. However, infection of certain cell types can result in high viral gene transcription and either cytolysis or neoplastic transformation. While infection by polyomavirus is common in humans and many animals, major questions regarding viral persistence of most polyomaviruses remain unanswered. Specifically, identification of target cells for viral infection and the mechanisms polyomaviruses employ to maintain viral genomes within cells are important not only in ascribing causality to polyomaviruses in disease, but in understanding specific mechanisms by which they cause disease...
September 6, 2016: Journal of General Virology
Zygmynt Zdrojewicz, Karolina Kasperska, Marta Lewandowska
Contraception is important from a health, psychological and socioeconomic point of view. Due to the fact that male-based contraceptive methods are mostly represented by condoms and vasectomy, researchers are working on the new solutions, which could let the men be more involved in a conscious family planning. In this review we will present the current state of knowledge on this subject. There is a lot going on in the field of hormonal contraception. Studies including testosterone, progestins, synthetic androgens and other derivatives are on a different stages of clinical trials and mostly demonstrate high efficacy rates...
August 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Zygmynt Zdrojewicz, Karolina Kasperska, Marta Lewandowska
Contraception is important from a health, psychological and socioeconomic point of view. Due to the fact that male-based contraceptive methods are mostly represented by condoms and vasectomy, researchers are working on the new solutions, which could let the men be more involved in a conscious family planning. In this review we will present the current state of knowledge on this subject. There is a lot going on in the field of hormonal contraception. Studies including testosterone, progestins, synthetic androgens and other derivatives are on a different stages of clinical trials and mostly demonstrate high efficacy rates...
July 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Seika Amemiya, Takao Yamaguchi, Taki Sakai, Yuichi Hashimoto, Tomomi Noguchi-Yachide
Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N(6)-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure-activity relationships of these inhibitors...
2016: Chemical & Pharmaceutical Bulletin
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