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Discovery of an MLLT1/3 YEATS Domain Chemical Probe

preprint
submitted on 14.09.2018 and posted on 18.09.2018 by Moses Moustakim, Thomas Christott, Octovia P. Monteiro, James Bennett, Charline Giroud, Jennifer Ward, Catherine Rogers, Paul Smith, Ioanna Panagakou, Laura Diaz Saez, Suet Ling Felce, Vicki Gamble, Carina Gileadi, Nadia Halidi, David Heidenreich, Apirat Chaikuad, Stefan Knapp, Kilian Huber, Gillian Farnie, Jag Heer, Nenad Manevski, Gennady Poda, Rima Al-awar, Darren J. Dixon, Paul E. Brennan, Oleg Fedorov

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.

Funding

Wellcome Trust: 106169/ZZ14/Z

History

Email Address of Submitting Author

moses.moustakim@mssm.edu

Institution

University of Oxford

Country

UK

ORCID For Submitting Author

0000-0002-5006-5684

Declaration of Conflict of Interest

N. Manevski and J. Heer are employees and hold shares in UCB Pharma Ltd.

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in Angewandte Chemie International Edition

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