Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1)

HAT1
is a central regulator of chromatin synthesis that
acetylates
nascent histone H4. To ascertain whether targeting HAT1 is a viable
anticancer treatment strategy, we sought to identify small-molecule
inhibitors of HAT1 by developing a high-throughput HAT1 acetyl-click
assay. Screening of small-molecule libraries led to the discovery
of multiple riboflavin analogs that inhibited HAT1 enzymatic activity.
Compounds were refined by synthesis and testing of over 70 analogs,
which yielded structure–activity relationships. The isoalloxazine
core was required for enzymatic inhibition, whereas modifications
of the ribityl side chain improved enzymatic potency and cellular
growth suppression. One compound (JG-2016 [24a]) showed
relative specificity toward HAT1 compared to other acetyltransferases,
suppressed the growth of human cancer cell lines, impaired enzymatic
activity in cellulo, and interfered with tumor growth.
This is the first report of a small-molecule inhibitor of the HAT1
enzyme complex and represents a step toward targeting this pathway
for cancer therapy.