Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

Autor: Moustakim M; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK., Christott T; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, 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 & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, 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; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, 60438, Frankfurt am Main, Germany., Chaikuad A; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.; 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.; Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, 60438, Frankfurt am Main, Germany., Huber KVM; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK., Farnie G; Structural Genomics Consortium & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK., Heer J; UCB Pharma Ltd, Slough, SL1 3WE, UK., Manevski N; UCB Pharma Ltd, Slough, SL1 3WE, UK., Poda G; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada., Al-Awar R; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada., Dixon DJ; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK., Brennan PE; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.; Alzheimer's Research (UK) Oxford Drug Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK., Fedorov O; Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2018 Dec 10; Vol. 57 (50), pp. 16302-16307. Date of Electronic Publication: 2018 Nov 16.
DOI: 10.1002/anie.201810617
Abstrakt: 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.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
Externí odkaz: