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Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.
Bradley, Erin; Fusani, Lucia; Chung, Chun-Wa; Craggs, Peter D; Demont, Emmanuel H; Humphreys, Philip G; Mitchell, Darren J; Phillipou, Alex; Rioja, Inmaculada; Shah, Rishi R; Wellaway, Christopher R; Prinjha, Rab K; Palmer, David S; Kerr, William J; Reid, Marc; Wall, Ian D; Cookson, Rosa.
Afiliação
  • Bradley E; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Fusani L; Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • Chung CW; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Craggs PD; Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • Demont EH; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Humphreys PG; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Mitchell DJ; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Phillipou A; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Rioja I; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Shah RR; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Wellaway CR; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Prinjha RK; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Palmer DS; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Kerr WJ; GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
  • Reid M; Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • Wall ID; Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • Cookson R; Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
J Med Chem ; 66(23): 15728-15749, 2023 12 14.
Article em En | MEDLINE | ID: mdl-37967462
ABSTRACT
Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Nucleares Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Reino Unido
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Nucleares Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Reino Unido