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Potent and selective bivalent inhibitors of BET bromodomains.
Waring, Michael J; Chen, Huawei; Rabow, Alfred A; Walker, Graeme; Bobby, Romel; Boiko, Scott; Bradbury, Rob H; Callis, Rowena; Clark, Edwin; Dale, Ian; Daniels, Danette L; Dulak, Austin; Flavell, Liz; Holdgate, Geoff; Jowitt, Thomas A; Kikhney, Alexey; McAlister, Mark; Méndez, Jacqui; Ogg, Derek; Patel, Joe; Petteruti, Philip; Robb, Graeme R; Robers, Matthew B; Saif, Sakina; Stratton, Natalie; Svergun, Dmitri I; Wang, Wenxian; Whittaker, David; Wilson, David M; Yao, Yi.
Afiliación
  • Waring MJ; AstraZeneca, Alderley Park, UK.
  • Chen H; Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK.
  • Rabow AA; AstraZeneca, Waltham, Massachusetts, USA.
  • Walker G; AstraZeneca, Alderley Park, UK.
  • Bobby R; AstraZeneca, Alderley Park, UK.
  • Boiko S; AstraZeneca, Alderley Park, UK.
  • Bradbury RH; AstraZeneca, Waltham, Massachusetts, USA.
  • Callis R; AstraZeneca, Alderley Park, UK.
  • Clark E; AstraZeneca, Alderley Park, UK.
  • Dale I; AstraZeneca, Waltham, Massachusetts, USA.
  • Daniels DL; AstraZeneca, Alderley Park, UK.
  • Dulak A; Promega Corporation, Madison, Wisconsin, USA.
  • Flavell L; AstraZeneca, Waltham, Massachusetts, USA.
  • Holdgate G; AstraZeneca, Alderley Park, UK.
  • Jowitt TA; AstraZeneca, Alderley Park, UK.
  • Kikhney A; Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
  • McAlister M; European Molecular Biology Laboratory, Hamburg, Germany.
  • Méndez J; AstraZeneca, Alderley Park, UK.
  • Ogg D; Promega Corporation, Madison, Wisconsin, USA.
  • Patel J; AstraZeneca, Alderley Park, UK.
  • Petteruti P; AstraZeneca, Waltham, Massachusetts, USA.
  • Robb GR; AstraZeneca, Waltham, Massachusetts, USA.
  • Robers MB; AstraZeneca, Alderley Park, UK.
  • Saif S; Promega Corporation, Madison, Wisconsin, USA.
  • Stratton N; AstraZeneca, Waltham, Massachusetts, USA.
  • Svergun DI; AstraZeneca, Alderley Park, UK.
  • Wang W; European Molecular Biology Laboratory, Hamburg, Germany.
  • Whittaker D; AstraZeneca, Waltham, Massachusetts, USA.
  • Wilson DM; AstraZeneca, Alderley Park, UK.
  • Yao Y; AstraZeneca, Alderley Park, UK.
Nat Chem Biol ; 12(12): 1097-1104, 2016 Dec.
Article en En | MEDLINE | ID: mdl-27775716
Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteínas Nucleares / Bibliotecas de Moléculas Pequeñas / Dominios Proteicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteínas Nucleares / Bibliotecas de Moléculas Pequeñas / Dominios Proteicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos