Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9
Christott T., Bennett J., Coxon C., Monteiro O., Giroud C., Beke V., Felce SL., Gamble V., Gileadi C., Poda G., Al-awar R., Farnie G., Fedorov O.
<jats:p> Eleven-nineteen leukemia (ENL) contains an epigenetic reader domain (YEATS domain) that recognizes lysine acylation on histone 3 and facilitates transcription initiation and elongation through its interactions with the super elongation complex (SEC) and the histone methyl transferase DOT1L. Although it has been known for its role as a fusion protein in mixed lineage leukemia (MLL), overexpression of native ENL, and thus dysregulation of downstream genes in acute myeloid leukemia (AML), has recently been implicated as a driver of disease that is reliant on the epigenetic reader activity of the YEATS domain. We developed a peptide displacement assay (histone 3 tail with acylated lysine) and screened a small-molecule library totaling more than 24,000 compounds for their propensity to disrupt the YEATS domain–histone peptide binding. Among these, we identified a first-in-class dual inhibitor of ENL ( K<jats:sub>d</jats:sub> = 745 ± 45 nM) and its paralog AF9 ( K<jats:sub>d</jats:sub> = 523 ± 53 nM) and performed “SAR by catalog” with the aim of starting the development of a chemical probe for ENL. </jats:p>