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Discovery of an MLLT1/3 YEATS Domain Chemical Probe.
Moustakim, Moses; Christott, Thomas; Monteiro, Octovia P; Bennett, James; Giroud, Charline; Ward, Jennifer; Rogers, Catherine M; Smith, Paul; Panagakou, Ioanna; Díaz-Sáez, Laura; Felce, Suet Ling; Gamble, Vicki; Gileadi, Carina; Halidi, Nadia; Heidenreich, David; Chaikuad, Apirat; Knapp, Stefan; Huber, Kilian V M; Farnie, Gillian; Heer, Jag; Manevski, Nenad; Poda, Gennady; Al-Awar, Rima; Dixon, Darren J; Brennan, Paul E; Fedorov, Oleg.
Afiliação
  • Moustakim M; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Christott T; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Monteiro OP; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Bennett J; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Giroud C; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Ward J; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Rogers CM; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Smith P; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Panagakou I; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Díaz-Sáez L; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Felce SL; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Gamble V; Structural Genomics Consortium & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
  • Gileadi C; Structural Genomics Consortium & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
  • Halidi N; Structural Genomics Consortium & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
  • Heidenreich D; Structural Genomics Consortium & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
  • Chaikuad A; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, 60438, Frankfurt am Main, Germany.
  • Knapp S; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Huber KVM; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, 60438, Frankfurt am Main, Germany.
  • Farnie G; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Heer J; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, 60438, Frankfurt am Main, Germany.
  • Manevski N; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
  • Poda G; Structural Genomics Consortium & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
  • Al-Awar R; UCB Pharma Ltd, Slough, SL1 3WE, UK.
  • Dixon DJ; UCB Pharma Ltd, Slough, SL1 3WE, UK.
  • Brennan PE; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Fedorov O; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Angew Chem Int Ed Engl ; 57(50): 16302-16307, 2018 12 10.
Article em En | MEDLINE | ID: mdl-30288907
ABSTRACT
YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine-binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small-molecule chemical probe, SGC-iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC-iMLLT is a potent and selective inhibitor of MLLT1/3-histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small-molecule X-ray co-crystal structures with the MLLT1 YD are also reported. This first-in-class probe molecule can be used to understand MLLT1/3-associated biology and the therapeutic potential of small-molecule YD inhibitors.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Nucleares / Bibliotecas de Moléculas Pequenas / Proteínas de Neoplasias Limite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Reino Unido
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Nucleares / Bibliotecas de Moléculas Pequenas / Proteínas de Neoplasias Limite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Reino Unido