YEATS domains are epigenetic regulators and are recognised as readers of histone post-translational modifications (HPTM) alongside bromodomains, PHD fingers, and others. YEATS domains bind to lysine when the ε-carbon is acetylated or crotonylated. The YEATS-containing ENL links histone acetylation to active transcription and is a major driver of several types of acute leukaemia. Hence, ENL is a rational drug target to attenuate aberrant cell growth and malignancy.
An AlphaScreen assay that reports on the interaction of modified histone 3 with the YEATS domains of different proteins such as ENL was developed. The inhibitor screening was performed on a PHERAstar® microplate reader and uncovered a potent small molecule inhibitor interfering with the YEATS domains of ENL and AF9.
The PHERAstar FSX provided a powerful and versatile platform for the drug discovery campaign. Here, the inhibitor screening of tens of thousands of compounds for inhibiting the YEATS domain with an AlphaScreen® approach resulted in the identification of a potent small molecule inhibitor.