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Merck

Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

Angewandte Chemie (International ed. in English) (2018-10-06)
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
PMID30288907
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.

MATERIALS
Product Number
Brand
Product Description
SML2440
Sigma-Aldrich
SGC-iMLLT, ≥98% (HPLC)