Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors |
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| Institution: | 1. Institute of Molecular Biology and Pathology, CNR, 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. Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;1. Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece;2. Medical Physics Laboratory, Medical School, University of Ioannina, Greece;3. NMR Centre, Department of Chemistry, University of Ioannina, Greece;4. Section of Physical Chemistry, Department of Chemistry, University of Ioannina, Greece;1. Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;2. Department of Pharmacy, “G. D''Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy;3. Dipartimento di Sanità Pubblica e Malattie Infettive, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;4. Dipartimento di Medicina Sperimentale, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy;5. Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Vatan Caddesi, 34093 Fatih, Istanbul, Turkey;1. Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India;2. Departamento De Quimica Inorganica, Facultad de Farmacia, Universidad de Santiago, 15782 Santiago, Spain;1. State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China;2. Department of Chemistry, Nanchang University, Nanchang 330031, PR China;1. Pharmaceutical Gene Modulation, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands;2. Department of Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands |
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| 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. |
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| Keywords: | Histone acetyltransferase Inhibitor Acetylation Thiazole Gcn5 p300 |
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