Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain

Eleven-nineteen leukemia (ENL) protein is a histone acetylation
reader essential for disease maintenance in acute leukemias, in particular,
the mixed-lineage leukemia (MLL)-rearranged
leukemia. In this study, we carried out high-throughput screening
of a small-molecule library to identify inhibitors for the ENL YEATS
domain. Structure–activity relationship studies of the hits
and structure-based inhibitor design led to two compounds, 11 and 24, with IC50 values below 100 nM in
inhibiting the ENL–acetyl-H3 interaction. Both compounds, and
their precursor compound 7, displayed strong selectivity
toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells
and a synergistic effect with the bromodomain and extraterminal domain
inhibitor JQ1 in killing leukemia cells. Together, we have developed
selective chemical probes for the ENL YEATS domain, providing the
basis for further medicinal chemistry-based optimization to advance
both basic and translational research of ENL.