Acetylation is a key modulator of genome accessibility through decondensation of the chromatin structure.
The balance between acetylation and opposite deacetylation is, in fact, a prerequisite for several cell functions
and differentiation. To find modulators of the histone acetyltransferase Gcn5p, we performed a phenotypic
screening on a set of newly synthesized molecules derived from thiazole in budding yeast Saccharomyces
cereVisiae. We selected compounds that induce growth inhibition in yeast strains deleted in genes encoding
known histone acetyltransferases. A novel molecule CPTH2, cyclopentylidene-[4-(4′-chlorophenyl)thiazol-
2-yl)hydrazone, was selected based on its inhibitory effect on the growth of a gcn5Δ strain. We demonstrated
a specific chemical-genetic interaction between CPTH2 and HAT Gcn5p, indicating that CPTH2 inhibits
the Gcn5p dependent functional network. CPTH2 inhibited an in vitro HAT reaction, which is reverted by
increasing concentration of histone H3. In vivo, it decreased acetylation of bulk histone H3 at the specific
H3-AcK14 site. On the whole, our results demonstrate that CPTH2 is a novel HAT inhibitor modulating
Gcn5p network in vitro and in vivo