Objective
In recent years, YEATS (Yaf9, ENL, Af9, Taf41, Sas5) domains have emerged as readers of histone post-translational modifications (HPTM) alongside bromodomains, PHD fingers and others. Like bromo-domains, they recognise acylation on the ε-carbon atom of lysine and human YEATS domain containing proteins have been implicated as actors in a range of cancer types.
The paralogs MLLT1(aka ENL) and MLLT3(aka AF9) have long been known for their role in mixed lineage leukaemia (MLL) as fusion partners of KMT2A/MLL. However, the role of functional YEATS domains in MLL remains poorly understood.
Here, report the discovery of a selective inhibitor with sub-micromolar affinity for MLLT1/MLLT3 through a library screen and, based on this hit, the development and characterisation of chemical probe for the YEATS domains of MLLT1 and MLLT3: SGC-iMLLT is a potent inhibitor of both YEATS domains (Kd ≈ 100 nM, in vitro IC50 < 500 nM and cellular activity at < 1 μM for both MLLT1 and MLLT3) and selective over the other members of the human YEATS domain containing proteins as well as bromodomains.
