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 gcn5? 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. Because genetic mutations and translocations in HAT genes have been found in a number of epithelial and hematological tumors, we believe that CPTH2 and future derived compounds will be of great interest, taking into account the selectivity toward the Gcn5p functional network here demonstrated in yeast.
A Novel Histone Acetyltransferase Inhibitor Modulating Gcn5 Network: Cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl)hydrazone / Chimenti, Franco; Bizzarri, Bruna; Elias, Maccioni; Secci, Daniela; Bolasco, Adriana; Chimenti, Paola; Fioravanti, Rossella; Granese, Arianna; Carradori, Simone; Federica, Tosi; Ballario, Paola; S., Vernarecci; Patrizia, Filetici. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52 (2):(2009), pp. 530-536. [10.1021/jm800885d]