First-in-Class Selective Inhibitors of the Lysine Acetyltransferase KAT8

KAT8 is a lysine acetyltransferase primarily catalyzing
the acetylation
of Lys16 of histone H4 (H4K16). KAT8 dysregulation is linked to the
development and metastatization of many cancer types, including non-small
cell lung cancer (NSCLC) and acute myeloid leukemia (AML). Few KAT8
inhibitors have been reported so far, none of which displaying selective
activity. Based on the KAT3B/KDAC inhibitor C646, we developed a series
of N-phenyl-5-pyrazolone derivatives and identified
compounds 19 and 34 as low-micromolar KAT8
inhibitors selective over a panel of KATs and KDACs. Western blot,
immunofluorescence, and CETSA experiments demonstrated that both inhibitors
selectively target KAT8 in cells. Moreover, 19 and 34 exhibited mid-micromolar antiproliferative activity in
different cancer cell lines, including NSCLC and AML, without impacting
the viability of nontransformed cells. Overall, these compounds are
valuable tools for elucidating KAT8 biology, and their simple structures
make them promising candidates for future optimization studies.