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- Moses Moustakim
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Thomas Christott
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Octovia P. Monteiro
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- James Bennett
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Charline Giroud
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Jennifer Ward
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Catherine M. Rogers
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Paul Smith
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Ioanna Panagakou
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Laura Díaz‐Sáez
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Suet Ling Felce
- Structural Genomics Consortium & Botnar Research Centre University of Oxford Windmill Road Oxford OX3 7LD UK
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- Vicki Gamble
- Structural Genomics Consortium & Botnar Research Centre University of Oxford Windmill Road Oxford OX3 7LD UK
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- Carina Gileadi
- Structural Genomics Consortium & Botnar Research Centre University of Oxford Windmill Road Oxford OX3 7LD UK
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- Nadia Halidi
- Structural Genomics Consortium & Botnar Research Centre University of Oxford Windmill Road Oxford OX3 7LD UK
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- David Heidenreich
- Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences Johann Wolfgang Goethe-University 60438 Frankfurt am Main Germany
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- Apirat Chaikuad
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Stefan Knapp
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Kilian V. M. Huber
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Gillian Farnie
- Structural Genomics Consortium & Botnar Research Centre University of Oxford Windmill Road Oxford OX3 7LD UK
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- Jag Heer
- UCB Pharma Ltd Slough SL1 3WE UK
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- Nenad Manevski
- UCB Pharma Ltd Slough SL1 3WE UK
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- Gennady Poda
- Drug Discovery Program Ontario Institute for Cancer Research Toronto ON Canada
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- Rima Al‐awar
- Drug Discovery Program Ontario Institute for Cancer Research Toronto ON Canada
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- Darren J. Dixon
- Department of Chemistry University of Oxford Chemistry Research Laboratory Mansfield Road Oxford OX1 3TA UK
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- Paul E. Brennan
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
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- Oleg Fedorov
- Structural Genomics Consortium & Target Discovery Institute University of Oxford, NDMRB Old Road Campus Oxford, OX3 7DQ & OX3 7FZ UK
説明
<jats:title>Abstract</jats:title><jats:p>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, <jats:bold>SGC</jats:bold>‐<jats:bold>iMLLT</jats:bold>, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). <jats:bold>SGC‐iMLLT</jats:bold> 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.</jats:p>
収録刊行物
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- Angewandte Chemie International Edition
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Angewandte Chemie International Edition 57 (50), 16302-16307, 2018-11-16
Wiley