A novel histone acetyltransferase inhibitor modulating Gcn5 network: cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl)hydrazone.
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.
Chimenti
Franco
F
Dipartimento di Chimica e Tecnologie del Farmaco, Universita degli Studi di Roma La Sapienza, P. le A. Moro 5, 00185 Rome, Italy.
Bizzarri
Bruna
B
Maccioni
Elias
E
Secci
Daniela
D
Bolasco
Adriana
A
Chimenti
Paola
P
Fioravanti
Rossella
R
Granese
Arianna
A
Carradori
Simone
S
Tosi
Federica
F
Ballario
Paola
P
Vernarecci
Stefano
S
Filetici
Patrizia
P
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
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