Difluoromethyl-1,3,4-oxadiazoles are slow-binding substrate analog inhibitors of histone deacetylase 6 with unprecedented isotype selectivity
Articolo
Data di Pubblicazione:
2023
Citazione:
Difluoromethyl-1,3,4-oxadiazoles are slow-binding substrate analog inhibitors of histone deacetylase 6 with unprecedented isotype selectivity / E. Cellupica, G. Caprini, P. Cordella, C. Cukier, G. Fossati, M. Marchini, I. Rocchio, G. Sandrone, M.A. Vanoni, B. Vergani, K. Źrubek, A. Stevenazzi, C. Steinkühler. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 299:1(2023 Jan), pp. 102800.1-102800.7. [10.1016/j.jbc.2022.102800]
Abstract:
Histone deacetylase 6 (HDAC6) is an attractive drug development target due to its role in the immune response, neuropathy, and cancer. Knock-out mice develop normally and have no apparent phenotype, suggesting that selective inhibitors should have an excellent therapeutic window. Unfortunately, current HDAC6 inhibitors have only moderate selectivity and may inhibit other HDAC subtypes at high concentrations, potentially leading to side effects. Recently, substituted oxadiazoles have attracted attention as a promising novel HDAC inhibitor chemotype, but their mechanism of action is unknown. Here, we show that compounds containing a difluoromethyl-1,3,4-oxadiazole (DFMO) moiety are potent, single-digit nanomolar inhibitors with an unprecedented, greater than 104-fold selectivity for HDAC6 over all other HDAC subtypes. By combining kinetics, X-ray crystallography, and mass spectrometry, we found that DFMO-derivatives are slow-binding substrate analogs of HDAC6 that undergo an enzyme-catalyzed ring opening reaction, forming a tight, long-lived enzyme-inhibitor complex. The elucidation of the mechanism of action of DFMO-derivatives paves the way for the rational design of highly selective inhibitors of HDAC6 and possibly of other HDAC subtypes as well with potentially important therapeutic implications.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Histone Deacetylase (HDAC); Histone Deacetylase 6 (HDAC6); Histone Deacetylase Inhibitor (HDI); X-ray crystallography; Zinc Binding Group (ZBG); difluoro methyl oxadiazole (DFMO); epigenetics; inhibition mechanism; mechanism-based inhibitor
Elenco autori:
E. Cellupica, G. Caprini, P. Cordella, C. Cukier, G. Fossati, M. Marchini, I. Rocchio, G. Sandrone, M.A. Vanoni, B. Vergani, K. Źrubek, A. Stevenazzi, C. Steinkühler
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