Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors

Daniela Secci; Simone Carradori; Bruna Bizzarri; Adriana Bolasco; Paola Ballario; Zoi Patramani; Paola Fragapane; Stefano Vernarecci; Claudia Canzonetta; Patrizia Filetici

doi:10.1016/j.bmc.2014.01.022

Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors

Bioorg Med Chem. 2014 Mar 1;22(5):1680-9. doi: 10.1016/j.bmc.2014.01.022. Epub 2014 Jan 26.

Affiliations

¹ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
² Institute Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnologies C. Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
³ Institute of Molecular Biology and Pathology, CNR, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
⁴ 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.

PMID: 24513187
DOI: 10.1016/j.bmc.2014.01.022

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.

Keywords: Acetylation; Gcn5; Histone acetyltransferase; Inhibitor; Thiazole; p300.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Cell Line, Tumor
HeLa Cells
Histone Acetyltransferases / antagonists & inhibitors*
Histone Acetyltransferases / chemical synthesis*
Humans
Thiazoles / chemical synthesis*
Thiazoles / chemistry

Substances

Thiazoles
Histone Acetyltransferases