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Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer 期刊论文
NATURE, 2020, 578 (7794) : 306-+
作者:  Harper, Gavin;  Sommerville, Roberto;  Kendrick, Emma;  Driscoll, Laura;  Slater, Peter;  Stolkin, Rustam;  Walton, Allan;  Christensen, Paul;  Heidrich, Oliver;  Lambert, Simon;  Abbott, Andrew;  Ryder, Karl;  Gaines, Linda;  Anderson, Paul
收藏  |  浏览/下载:21/0  |  提交时间:2020/07/03

ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.


Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi(1-5). Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice(6), the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions(7-9) and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported(10,11), suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment(10-13). Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075(14). Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.


  
The role of plant phenology in stomatal ozone flux modeling 期刊论文
GLOBAL CHANGE BIOLOGY, 2018, 24 (1) : 235-248
作者:  Anav, Alessandro;  Liu, Qiang;  De Marco, Alessandra;  Proietti, Chiara;  Savi, Flavia;  Paoletti, Elena;  Piao, Shilong
收藏  |  浏览/下载:17/0  |  提交时间:2019/04/09
dormancy date  green-up date  ozone  phytotoxic ozone dose  risk assessment  stomatal conductance  
West Valley Demonstration Project Annual Site Environmental Report (ASER) for Calendar Year 2015 科技报告
来源:US Department of Energy (DOE). 出版年: 2016
作者:  Rendall, John D.;  Steiner, Alison F.;  Pendl, Michael P.;  Biedermann, Charles A.;  Steiner, II, Robert E.;  Fox, James R.;  Hoch, Jerald J.;  Wrotniak, Chester M.;  Werchowski, Rebecca L.
收藏  |  浏览/下载:36/0  |  提交时间:2019/04/05
West Valley Demonstration Project  WVDP  Annual Site Environmental Report  ASER  Calendar Year 2015  Ambient Air Samplers  Demolition  DOE/NYSERDA Consent Decree  Dose Assessment  Dose from Airborne Emissions  Dose from Waterborne Releases  Dose to Biota  
West Valley Demonstration Project Annual Site Environmental Report (ASER) for Calendar Year 2014 科技报告
来源:US Department of Energy (DOE). 出版年: 2015
作者:  Rendall, John D.;  Steiner, Alison F.;  Pendl, Michael P.;  Biedermann, Charles A.;  Steiner, II, Robert E.;  Fox, James R.;  Hoch, Jerald J.;  Werchowski, Rebecca L.
收藏  |  浏览/下载:18/0  |  提交时间:2019/04/05
West Valley Demonstration Project  WVDP  Annual Site Environmental Report  ASER  Calendar Year 2014  DOE/NYSERDA Consent Decree  Dose Assessment  Dose from Airborne Emissions  Dose from Waterborne Releases  Dose to Biota  Drinking Water  Environmental Cha  
West Valley Demonstration Project Annual Site Environmental Report Calendar Year 2013 科技报告
来源:US Department of Energy (DOE). 出版年: 2014
作者:  Rendall, John D.;  Steiner, Alison F.;  Pendl, Michael P.
收藏  |  浏览/下载:26/0  |  提交时间:2019/04/05
West Valley Demonstration Project  WVDP  Annual Site Environmental Report  ASER  Calendar Year 2013  CH2M HILL • B&W West Valley  LLC  DE-EM0001529  Public Health and Safety and the Environment Are Protected  Airborne and Waterborne Releases to the MEOSI  Climate Change  DOE/NYSERDA Consent Decree  Dose Assessment  Dose to Biota  Drinking Water  Environmental Characterization Support Services  Environmental Compliance  Environmental Management System: EMS  Environmental Monitoring  Groundwater Protection Program  High-Level Waste (HLW) Canister Interim Storage System  HLW canister storage pad  National Emissions Standards for Hazardous Air Pollutants  NESHAP  National Environmental Policy Act  NEPA  North Plateau Full-Scale Permeable Treatment Wall  PTW  Nuclear Regulatory Commission (NRC)-Licensed Disposal Area  NDA  Performance Indicators  Phase 1 Decommissioning and Facility Disposition Contract  Phase 1 Studies  Quality Assurance  Record of Decision  ROD  Resource Conservation and Recovery Act  RCRA  Safety Success  Site Sustainability Plan  SSP  State Pollutant Discharge Elimination System (SPDES) Permit Noncompliance  SPDES  Tank and Vault Drying System  T&VDS  Vertical Storage Casks  VSC  Waste Minimization and Pollution Prevention  Waste Tank Farm  WTF  Waste-Incidental-to-Reprocessing  WIR  
Nevada National Security Site Environmental Report 2012 科技报告
来源:US Department of Energy (DOE). 出版年: 2013
作者:  Wills, Cathy
收藏  |  浏览/下载:11/0  |  提交时间:2019/04/05
NNSS  public dose assessment  environmental  compliance  remediation  radiological  monitoring  air  groundwater  biota  waste management  cultural resources  protection