title: A novel histone acetyltransferase inhibitor modulating Gcn5 network: cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl)hydrazone.
abstract: 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 gcn5Delta 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.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Universita degli Studi di Roma La Sapienza, P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Chimenti
authors.forename: Bruna
authors.initials: B
authors.lastname: Bizzarri
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.forename: Daniela
authors.initials: D
authors.lastname: Secci
authors.forename: Adriana
authors.initials: A
authors.lastname: Bolasco
authors.forename: Paola
authors.initials: P
authors.lastname: Chimenti
authors.forename: Rossella
authors.initials: R
authors.lastname: Fioravanti
authors.forename: Arianna
authors.initials: A
authors.lastname: Granese
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.forename: Federica
authors.initials: F
authors.lastname: Tosi
authors.forename: Paola
authors.initials: P
authors.lastname: Ballario
authors.forename: Stefano
authors.initials: S
authors.lastname: Vernarecci
authors.forename: Patrizia
authors.initials: P
authors.lastname: Filetici
mesh_terms: D000107:Acetylation; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000235:genetics; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D009154:Mutation; D029701:Saccharomyces cerevisiae Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D000099224:p300-CBP-Associated Factor
chemical_list: D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D051548:Histone Acetyltransferases; D006657:Histones; D006835:Hydrazones; D029701:Saccharomyces cerevisiae Proteins; D013844:Thiazoles; C535240:cyclopentylidene-(4-(4'-chlorophenyl)thiazol-2-yl)hydrazone; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor