PHERAstar measures AlphaScreen assay to develop selective inhibitors for the human YEATS domains

Thomas Christott, Carmen Coxon, James Bennett, Charline Giroud, Octovia Monteiro, Oleg Fedorov, Structural Genomics Consortium, University of Oxford, UK 04/2018

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.



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