The YEATS domain containing proteins are an emerging class of epigenetic targets in drug discovery. Reported to bind acylated lysine residues, misregulation of these inter-species conserved proteins have been linked to the onset and progression of cancers such as acute myeloid leukaemia (AML). We herein report the discovery and characterisation of the first small molecule chemical probe inhibitor for the closely related YEATS domains of ENL (MLLT1) and AF9 (MLLT3). Our probe molecule is a potent nanomolar inhibitor of ENL/AF9 and displays selectivity over the two other human YEATS domain containing proteins (YEATS2 and GAS41). Evidence of cellular-target engagement of ENL was explored through a NanoBRET displacement assay. Commensurate with recent reports of ENL knockdowns, our probe molecule has been investigated for anti-cancer activity in leukemic cell lines and synergestic effects when dosed in combination with BET bromodomain inhibitors such as (+)-JQ1. Taken together our probe molecule can be used as a novel tool to ENL/AF9 associated biology.

Development of a YEATS-domain chemical probe

256th National Meeting (2018)

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