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Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers.
Anthony, Nahoum G; Baiget, Jessica; Berretta, Giacomo; Boyd, Marie; Breen, David; Edwards, Joanne; Gamble, Carly; Gray, Alexander I; Harvey, Alan L; Hatziieremia, Sophia; Ho, Ka Ho; Huggan, Judith K; Lang, Stuart; Llona-Minguez, Sabin; Luo, Jia Lin; McIntosh, Kathryn; Paul, Andrew; Plevin, Robin J; Robertson, Murray N; Scott, Rebecca; Suckling, Colin J; Sutcliffe, Oliver B; Young, Louise C; Mackay, Simon P.
Afiliación
  • Anthony NG; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Baiget J; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Berretta G; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Boyd M; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Breen D; WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, Scotland, United Kingdom.
  • Edwards J; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow , Garscube Estate, Switchback Road, Glasgow G61 1QH, Scotland, United Kingdom.
  • Gamble C; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Gray AI; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Harvey AL; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Hatziieremia S; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Ho KH; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Huggan JK; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Lang S; WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, Scotland, United Kingdom.
  • Llona-Minguez S; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Luo JL; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • McIntosh K; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Paul A; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Plevin RJ; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Robertson MN; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Scott R; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Suckling CJ; WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, Scotland, United Kingdom.
  • Sutcliffe OB; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Young LC; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
  • Mackay SP; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.
J Med Chem ; 60(16): 7043-7066, 2017 08 24.
Article en En | MEDLINE | ID: mdl-28737909
IKKß plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKß, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKß. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKß-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKß and to validate it in its own right as a target in inflammatory diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Pirroles / Inhibidores de Proteínas Quinasas / Quinasa I-kappa B Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Pirroles / Inhibidores de Proteínas Quinasas / Quinasa I-kappa B Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2017 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos