Discovery of an MLLT1/3 YEATS Domain Chemical Probe

Moses Moustakim; Thomas Christott; Octovia P Monteiro; James Bennett; Charline Giroud; Jennifer Ward; Catherine M Rogers; Paul Smith; Ioanna Panagakou; Laura Díaz-Sáez; Suet Ling Felce; Vicki Gamble; Carina Gileadi; Nadia Halidi; David Heidenreich; Apirat Chaikuad; Stefan Knapp; Kilian V M Huber; Gillian Farnie; Jag Heer; Nenad Manevski; Gennady Poda; Rima Al-Awar; Darren J Dixon; Paul E Brennan; Oleg Fedorov

doi:10.1002/anie.201810617

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. Epub 2018 Nov 16.

Authors

Moses Moustakim^{1

2}, Thomas Christott¹, Octovia P Monteiro¹, James Bennett¹, Charline Giroud¹, Jennifer Ward¹, Catherine M Rogers¹, Paul Smith¹, Ioanna Panagakou¹, Laura Díaz-Sáez¹, Suet Ling Felce³, Vicki Gamble³, Carina Gileadi³, Nadia Halidi³, David Heidenreich⁴, Apirat Chaikuad^{1

4}, Stefan Knapp^{1

4}, Kilian V M Huber¹, Gillian Farnie³, Jag Heer⁵, Nenad Manevski⁵, Gennady Poda^{6

7}, Rima Al-Awar^{6

8}, Darren J Dixon², Paul E Brennan^{1

9}, Oleg Fedorov¹

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Crystallography, X-Ray
Histones / metabolism
Humans
Molecular Docking Simulation
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / chemistry*
Neoplasm Proteins / metabolism
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / chemistry*
Nuclear Proteins / metabolism
Protein Domains
Protein Interaction Maps / drug effects
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology
Transcription Factors / antagonists & inhibitors*
Transcription Factors / chemistry*
Transcription Factors / metabolism

Substances

Histones
MLLT1 protein, human
MLLT3 protein, human
Neoplasm Proteins
Nuclear Proteins
Small Molecule Libraries
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding