The Importance of the "Time Factor" for the Evaluation of Inhibition Mechanisms: The Case of Selected HDAC6 Inhibitors
Articolo
Data di Pubblicazione:
2023
Citazione:
The Importance of the "Time Factor" for the Evaluation of Inhibition Mechanisms: The Case of Selected HDAC6 Inhibitors / E. Cellupica, G. Caprini, G. Fossati, D. Mirdita, P. Cordella, M. Marchini, I. Rocchio, G. Sandrone, A. Stevenazzi, B. Vergani, C. Steinkühler, M.A. Vanoni. - In: BIOLOGY. - ISSN 2079-7737. - 12:8(2023 Jul 26), pp. 1049.1-1049.18. [10.3390/biology12081049]
Abstract:
Histone deacetylases (HDACs) participate with histone acetyltransferases in the modulation
of the biological activity of a broad array of proteins, besides histones. Histone deacetylase 6 is unique
among HDAC as it contains two catalytic domains, an N-terminal microtubule binding region and a
C-terminal ubiquitin binding domain. Most of its known biological roles are related to its protein
lysine deacetylase activity in the cytoplasm. The design of specific inhibitors is the focus of a large
number of medicinal chemistry programs in the academy and industry because lowering HDAC6
activity has been demonstrated to be beneficial for the treatment of several diseases, including cancer,
and neurological and immunological disorders. Here, we show how re-evaluation of the mechanism
of action of selected HDAC6 inhibitors, by monitoring the time-dependence of the onset and relief of
the inhibition, revealed instances of slow-binding/slow-release inhibition. The same approach, in
conjunction with X-ray crystallography, in silico modeling and mass spectrometry, helped to propose
a model of inhibition of HDAC6 by a novel difluoromethyloxadiazole-based compound that was
found to be a slow-binding substrate analog of HDAC6, giving rise to a tightly bound, long-lived
inhibitory derivative.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
cancer; difluoromethyloxadiazoles; histone deacetylase; histone deacetylase 6; hydroxamates; immunomodulation; inhibition; kinetics; medicinal chemistry; neurodegeneration
Elenco autori:
E. Cellupica, G. Caprini, G. Fossati, D. Mirdita, P. Cordella, M. Marchini, I. Rocchio, G. Sandrone, A. Stevenazzi, B. Vergani, C. Steinkühler, M.A. Vanoni
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