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Angew Chem Int Ed Engl. 2018 Dec 10;57(50):16302-16307. doi: 10.1002/anie.201810617. Epub 2018 Nov 16.

Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

Author information

1
Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7DQ &, OX3 7FZ, UK.
2
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
3
Structural Genomics Consortium & Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
4
Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, 60438, Frankfurt am Main, Germany.
5
UCB Pharma Ltd, Slough, SL1 3WE, UK.
6
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
7
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
8
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
9
Alzheimer's Research (UK) Oxford Drug Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK.

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.

KEYWORDS:

MLLT1; MLLT3; YEATS; chemical probes; epigenetics

PMID:
30288907
PMCID:
PMC6348381
DOI:
10.1002/anie.201810617
[Indexed for MEDLINE]
Free PMC Article

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