Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

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.

• Authors: 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
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 57 Issue 50 Pg. 16302-16307 (12 10 2018) ISSN: 1521-3773 [Electronic] Germany
• PMID: 30288907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

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

Topics

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