2. Academic Validation
  3. Discovery of an MLLT1/3 YEATS Domain Chemical Probe

Discovery of an MLLT1/3 YEATS Domain Chemical Probe

  • Angew Chem Int Ed Engl. 2018 Dec 10;57(50):16302-16307. doi: 10.1002/anie.201810617.
Moses Moustakim 1 2,  Thomas Christott 1,  Octovia P Monteiro 1,  James Bennett 1,  Charline Giroud 1,  Jennifer Ward 1,  Catherine M Rogers 1,  Paul Smith 1,  Ioanna Panagakou 1,  Laura Díaz-Sáez 1,  Suet Ling Felce 3,  Vicki Gamble 3,  Carina Gileadi 3,  Nadia Halidi 3,  David Heidenreich 4,  Apirat Chaikuad 1 4,  Stefan Knapp 1 4,  Kilian V M Huber 1,  Gillian Farnie 3,  Jag Heer 5,  Nenad Manevski 5,  Gennady Poda 6 7,  Rima Al-Awar 6 8,  Darren J Dixon 2,  Paul E Brennan 1 9,  Oleg Fedorov 1
Affiliations

Affiliations

  • 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.
PMID: 30288907 DOI: 10.1002/anie.201810617
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.

Figures
Products