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https://www.readbyqxmd.com/read/29907650/jak2-is-dispensable-for-maintenance-of-jak2-mutant-b-cell-acute-lymphoblastic-leukemias
#1
Sang-Kyu Kim, Deborah A Knight, Lisa R Jones, Stephin Vervoort, Ashley P Ng, John F Seymour, James E Bradner, Michaela Waibel, Lev Kats, Ricky W Johnstone
Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL...
June 15, 2018: Genes & Development
https://www.readbyqxmd.com/read/29899872/hitting-two-oncogenic-machineries-in-cancer-cells-cooperative-effects-of-the-multi-kinase-inhibitor-ponatinib-and-the-bet-bromodomain-blockers-jq1-or-dbet1-on-human-carcinoma-cells
#2
Karin Bauer, Daniela Berger, Christoph C Zielinski, Peter Valent, Thomas W Grunt
In recent years, numerous new targeted drugs, including multi-kinase inhibitors and epigenetic modulators have been developed for cancer treatment. Ponatinib blocks a variety of tyrosine kinases including ABL and fibroblast growth factor receptor (FGFR), and the BET bromodomain (BRD) antagonists JQ1 and dBET1 impede MYC oncogene expression. Both drugs have demonstrated substantial anti-cancer efficacy against several hematological malignancies. Solid tumors, on the other hand, although frequently driven by FGFR and/or MYC, are often unresponsive to these drugs...
May 29, 2018: Oncotarget
https://www.readbyqxmd.com/read/29898995/ews-ets-driven-ewing-sarcoma-requires-bet-bromodomain-proteins
#3
Paradesi Naidu Gollavilli, Aishwarya Pawar, Kari Wilder-Romans, Natesan Ramakrishnan, Carl G Engelke, Vijaya L Dommeti, Pranathi M Krishnamurthy, Archana Nallasivam, Ingrid J Apel, Tianlei Xu, Zhaohui Qin, Felix Y Feng, Irfan A Asangani
The EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has been unsuccessful; however, identifying mediators of the EWS/ETS function could offer new therapeutic options. Here we describe the dependency of EWS/ETS-driven transcription upon chromatin reader BET bromdomain proteins and investigate the potential of BET inhibitors in treating EWS. EWS/FLI1 and EWS/ERG were found in a transcriptional complex with BRD4, and knockdown of BRD2/3/4 significantly impaired the oncogenic phenotype of EWS cells...
June 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29886462/-effects-of-pim-1-inhibitor-on-mouse-model-of-inflammatory-bowel-disease-induced-by-tnbs
#4
Rong Ou, Yueming Shen, Ya Zeng, Lingzhi Zou, Na Jiang, Meihua Xu
To explore the role of Pim-1 in the pathology of inflammatory bowel disease and the potential effect of Pim-1 inhibitor on treating such disease.
 Methods: Forty-five BALB/c mice were randomly divided into 5 groups (n=9): A normal control group, a inflammatory bowel disease group, two different dose of Pim-1 inhibitor treatment groups, and steroidhormone treatment group. The model of inflammatory bowel disease was induced by intracolonic administration of 2, 4, 6-trinitrobenzenestdfonic acid (TNBS) and ethanol mixture...
May 28, 2018: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
https://www.readbyqxmd.com/read/29884215/crebbp-ep300-bromodomains-are-critical-to-sustain-the-gata1-myc-regulatory-axis-in-proliferation
#5
Veronica Garcia-Carpizo, Sergio Ruiz-Llorente, Jacinto Sarmentero, Osvaldo Graña-Castro, David G Pisano, Maria J Barrero
BACKGROUND: The reported antitumor activity of the BET family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored. RESULTS: We report that the bromodomains of the histone acetyltransferases CREBBP/EP300 are critical to sustain the proliferation of human leukemia and lymphoma cell lines. EP300 is very abundant at super-enhancers in K562 and is coincident with sites of GATA1 and MYC occupancy...
June 8, 2018: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/29883070/altered-t-cell-subsets-and-transcription-factors-in-latent-autoimmune-diabetes-in-adults-with-sitagliptin-a-dipeptidyl-peptidase-4-inhibitor-a-one-year-open-label-randomized-controlled-trial
#6
Xia Wang, Lin Yang, Ying Cheng, Peilin Zheng, Jingping Hu, Gan Huang, Zhiguang Zhou
OBJECTIVE: Dipeptidyl Peptidase-4 Inhibitor was proved to improve glycemic control and βcell function in latent autoimmune diabetes in adults (LADA). The potential immune modulation mechanism is still unknown. Thus we tested T lymphocyte subsets and expression of relevant transcription factors in LADA patients with sitagliptin intervention for up to one-year study. METHODS: 40 LADA patients were randomly assigned to sitagliptin and (or) insulin treatment (SITA group, n=20) or insulin alone treatment (CONT group, n=20)...
June 8, 2018: Journal of Diabetes Investigation
https://www.readbyqxmd.com/read/29880921/mouse-medulloblastoma-driven-by-crispr-activation-of-cellular-myc
#7
BaoHan T Vo, Jin Ah Kwon, Chunliang Li, David Finkelstein, Beisi Xu, Brent A Orr, Charles J Sherr, Martine F Roussel
MYC-driven Group 3 (G3) medulloblastoma (MB) is the most aggressive of four molecular subgroups classified by transcriptome, genomic landscape and clinical outcomes. Mouse models that recapitulate human G3 MB all rely on retroviral vector-induced Myc expression driven by viral regulatory elements (Retro-Myc tumors). We used nuclease-deficient CRISPR/dCas9-based gene activation with combinatorial single guide RNAs (sgRNAs) to enforce transcription of endogenous Myc in Trp53-null neurospheres that were orthotopically transplanted into the brains of naïve animals...
June 7, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29802402/the-bet-inhibitor-i-bet762-inhibits-pancreatic-ductal-adenocarcinoma-cell-proliferation-and-enhances-the-therapeutic-effect-of-gemcitabine
#8
Fang Xie, Mei Huang, Xiansheng Lin, Chenhai Liu, Zhen Liu, Futao Meng, Chao Wang, Qiang Huang
As one of the most fatal malignancies, pancreatic ductal adenocarcinoma (PDAC) has significant resistance to the currently available treatment approaches. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC, has limited efficacy, which is attributed to innate/acquired resistance and the activation of prosurvival pathways. Here, we investigated the in vitro efficacy of I-BET762, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, in treating PDAC cell lines alone and in combination with gemcitabine (GEM)...
May 25, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29792310/bet-inhibition-overcomes-receptor-tyrosine-kinase-mediated-cetuximab-resistance-in-hnscc
#9
Brandon Leonard, Toni M Brand, Rachel A O'Keefe, Eliot Lee, Yan Zang, Jacquelyn D Kemmer, Hua Li, Jennifer R Grandis, Neil E Bhola
Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK) including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK...
May 23, 2018: Cancer Research
https://www.readbyqxmd.com/read/29789664/the-bet-bromodomain-inhibitor-apabetalone-induces-apoptosis-of-latent-hiv-1-reservoir-cells-following-viral-reactivation
#10
Xuan-Xuan Zhang, Jian Lin, Tai-Zhen Liang, Heng Duan, Xing-Hua Tan, Bao-Min Xi, Lin Li, Shu-Wen Liu
The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol...
May 22, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29784003/bi-directional-regulation-of-cartilage-metabolism-by-inhibiting-bet-proteins-analysis-of-the-effect-of-i-bet151-on-human-chondrocytes-and-murine-joints
#11
Jin Dai, Sheng Zhou, Qiting Ge, Jinzhong Qin, Dongyang Chen, Zhihong Xu, Dongquan Shi, Jianxin Li, Huangxian Ju, Yi Cao, Minghao Zheng, Chao Jun Li, Xiang Gao, Huajian Teng, Qing Jiang
BACKGROUND: Proinflammatory cytokines, which can upregulate the expression of matrix-degrading enzymes in chondrocytes, play important roles in the development of osteoarthritis. And a BET protein inhibitor, I-BET151, has been shown to exert an anti-inflammatory effect by repressing the BET protein-mediated expression of inflammatory genes. Our objective is to investigate the effect of I-BET151 on a surgical mouse model of osteoarthritis (OA) and human chondrocytes. METHODS: We first treated a surgical mouse model of OA with I-BET151 once per day and evaluated the knee joints at 6 and 8 weeks after treatment...
May 21, 2018: Journal of Orthopaedic Surgery and Research
https://www.readbyqxmd.com/read/29782963/bet-inhibition-by-jq1-alleviates-streptozotocin-induced-diabetic-cardiomyopathy
#12
Miao Guo, Hong-Xia Wang, Wen-Jun Chen
Diabetic cardiomyopathy is a cascade of complex events leading to eventual heart failure in diabetes. JQ1, one of Bromodomain and extra-terminal domain (BET) protein inhibitors, has exerted therapeutic effects on cancer proliferation, inflammation and cardiovascular disease. Recently, JQ1 was reported to protect mice from bleomycin-induced lung fibrosis and reverse the fibrotic response in carbon tetrachloride-induced liver fibrosis. However, its role in diabetic cardiomyopathy remains to be clarified. Our results indicated that JQ1 treatment suppressed cardiac fibrosis and improved cardiac function in a STZ-induced diabetic mouse model...
May 18, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29777912/a-super-enhancer-maintains-homeostatic-expression-of-regnase-1
#13
Riyun Yang, Yuanyuan Wu, Yue Ming, Yuanpei Xu, Shouyan Wang, Jianbo Shen, Chenlu Wang, Xia Chen, Yongming Wang, Renfang Mao, Yihui Fan
Regnase-1 is not only a key component in maintaining intracellular homeostasis but also a critical negative regulator in preventing autoimmune diseases and cancer development. To keep homeostatic state, Regnase-1 has to be maintained at a desired level in multiple cell types. However, the molecular mechanism of keeping a certain transcriptional level of Reganase-1 is largely unknown. In this study, we found a super-enhancer (Reg-1-SE) around Regnase-1 gene is able to control the homeostatic expression of Regnase-1...
May 16, 2018: Gene
https://www.readbyqxmd.com/read/29777702/microrna-608-inhibits-human-hepatocellular-carcinoma-cell-proliferation-via-targeting-the-bet-family-protein-brd4
#14
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
#15
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/29776910/the-bet-inhibitor-birabresib-is-safe-in-patients-with-solid-tumors
#16
(no author information available yet)
Birabresib achieved partial responses in 3 of 10 patients with NUT midline carcinoma.
May 18, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29767555/protective-effect-of-the-bet-protein-inhibitor-jq1-in-cisplatin-induced-nephrotoxicity
#17
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
#18
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/29760405/arid1a-mutation-sensitizes-most-ovarian-clear-cell-carcinomas-to-bet-inhibitors
#19
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/29760044/nk-cells-mediate-synergistic-antitumor-effects-of-combined-inhibition-of-hdac6-and-bet-in-a-sclc-preclinical-model
#20
Yan Liu, Yuyang Li, Shengwu Liu, Dennis O Adeegbe, Camilla L Christensen, Max M Quinn, Ruben Dries, Shiwei Han, Kevin Buczkowski, Xiaoen Wang, Ting Chen, Peng Gao, Hua Zhang, Fei Li, Peter S Hammerman, James E Bradner, Steven N Quayle, Kwok-Kin Wong
Small cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1...
May 14, 2018: Cancer Research
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