Your browser doesn't support javascript.
loading
Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.
Vazquez-Rodriguez, Saleta; Wright, Miranda; Rogers, Catherine M; Cribbs, Adam P; Velupillai, Srikannathasan; Philpott, Martin; Lee, Henry; Dunford, James E; Huber, Kilian V M; Robers, Matthew B; Vasta, James D; Thezenas, Marie-Laetitia; Bonham, Sarah; Kessler, Benedikt; Bennett, James; Fedorov, Oleg; Raynaud, Florence; Donovan, Adam; Blagg, Julian; Bavetsias, Vassilios; Oppermann, Udo; Bountra, Chas; Kawamura, Akane; Brennan, Paul E.
Afiliação
  • Vazquez-Rodriguez S; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Wright M; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Rogers CM; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
  • Cribbs AP; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Velupillai S; Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, NIHR Oxford BRC, University of Oxford, Oxford, OX3 7DQ, UK.
  • Philpott M; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Lee H; Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, NIHR Oxford BRC, University of Oxford, Oxford, OX3 7DQ, UK.
  • Dunford JE; Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, NIHR Oxford BRC, University of Oxford, Oxford, OX3 7DQ, UK.
  • Huber KVM; Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, NIHR Oxford BRC, University of Oxford, Oxford, OX3 7DQ, UK.
  • Robers MB; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Vasta JD; Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI, 53711, USA.
  • Thezenas ML; Promega Corporation, 2800 Woods Hollow Road, Fitchburg, WI, 53711, USA.
  • Bonham S; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, Oxford, UK.
  • Kessler B; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, Oxford, UK.
  • Bennett J; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, Oxford, UK.
  • Fedorov O; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Raynaud F; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Donovan A; Cancer Research (UK) Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
  • Blagg J; Cancer Research (UK) Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
  • Bavetsias V; Cancer Research (UK) Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
  • Oppermann U; Cancer Research (UK) Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK.
  • Bountra C; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
  • Kawamura A; Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, NIHR Oxford BRC, University of Oxford, Oxford, OX3 7DQ, UK.
  • Brennan PE; FRIAS-Freiburg Institute of Advanced Studies, 79104, Freiburg, Germany.
Angew Chem Int Ed Engl ; 58(2): 515-519, 2019 01 08.
Article em En | MEDLINE | ID: mdl-30431220
ABSTRACT
Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Reino Unido
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Reino Unido