title: Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors.
abstract: Acetylation, which targets a broad range of histone and non-histone proteins, is a reversible mechanism and plays a critical role in eukaryotic genes activation/deactivation. Acetyltransferases are very well conserved through evolution. This allows the use of a simple model organism, such as budding yeast, for the study of their related processes and to discover specific inhibitors. Following a simple yeast-based chemogenetic approach, we have identified a novel HAT (histone acetyltransferase) inhibitor active both in vitro and in vivo. This new synthetic compound, 1-(4-(4-chlorophenyl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine, named BF1, showed substrate selectivity for histone H3 acetylation and inhibitory activity in vitro on recombinant HAT Gcn5 and p300. Finally, we tested BF1 on human cells, HeLa as control and two aggressive cancer cell lines: a neuroblastoma from neuronal tissue and glioblastoma from brain tumour. Both global acetylation of histone H3 and specific acetylation at lysine 18 (H3AcK18) were lowered by BF1 treatment. Collectively, our results show the efficacy of this novel HAT inhibitor and propose the utilization of BF1 as a new, promising tool for future pharmacological studies.
authors: Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Daniela
authors: D
authors: Secci
authors: Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Simone
authors: S
authors: Carradori
authors: Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Bruna
authors: B
authors: Bizzarri
authors: Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Adriana
authors: A
authors: Bolasco
authors: Institute Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnologies C. Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Paola
authors: P
authors: Ballario
authors: Institute of Molecular Biology and Pathology, CNR, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Zoi
authors: Z
authors: Patramani
authors: Institute of Molecular Biology and Pathology, CNR, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Paola
authors: P
authors: Fragapane
authors: Institute Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnologies C. Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Stefano
authors: S
authors: Vernarecci
authors: Institute Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnologies C. Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors: Claudia
authors: C
authors: Canzonetta
authors: Institute of Molecular Biology and Pathology, CNR, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: patrizia.filetici@uniroma1.it.
authors: Patrizia
authors: P
authors: Filetici
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis*; D006801:Humans; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D013844:Thiazoles; D051548:Histone Acetyltransferases
keywords: Acetylation; Gcn5; Histone acetyltransferase; Inhibitor; Thiazole; p300