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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.

Original publication

DOI

10.1002/anie.201810617

Type

Journal article

Journal

Angew Chem Int Ed Engl

Publication Date

10/12/2018

Volume

57

Pages

16302 - 16307

Keywords

MLLT1, MLLT3, YEATS, chemical probes, epigenetics, Crystallography, X-Ray, Histones, Humans, Molecular Docking Simulation, Neoplasm Proteins, Nuclear Proteins, Protein Domains, Protein Interaction Maps, Small Molecule Libraries, Transcription Factors