Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics. More specifically, we find that the chemical structure of a DMFO and the binding mode of its difluoroacetylhydrazide derivative are crucial in determining the predominant hydrolysis mechanism. Our findings provide additional insights into two different mechanisms of DFMO hydrolysis, thus contributing to a better understanding of the HDAC6 inhibition by oxadiazoles in disease modulation and therapeutic intervention.

Cellupica, E., Gaiassi, A., Rocchio, I., Rovelli, G., Pomarico, R., Sandrone, G., et al. (2024). Mechanistic and Structural Insights on Difluoromethyl-1,3,4-Oxadiazole Inhibitors of HDAC6. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 25(11), 1-12 [10.3390/ijms25115885].

Mechanistic and Structural Insights on Difluoromethyl-1,3,4-Oxadiazole Inhibitors of HDAC6

Airoldi, C;Palmioli, A;
2024

Abstract

Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics. More specifically, we find that the chemical structure of a DMFO and the binding mode of its difluoroacetylhydrazide derivative are crucial in determining the predominant hydrolysis mechanism. Our findings provide additional insights into two different mechanisms of DFMO hydrolysis, thus contributing to a better understanding of the HDAC6 inhibition by oxadiazoles in disease modulation and therapeutic intervention.
Articolo in rivista - Articolo scientifico
histone deacetylase 6 (HDAC6); difluoromethyl-1,3,4-oxadiazole (DFMO); non hydroxamic inhibitors; NMR; LC-MS; X-ray crystallography; enzyme kinetics; DFMO hydrolysis; difluoroacetylhydrazide (DFAcH)
English
28-mag-2024
2024
25
11
1
12
5885
open
Cellupica, E., Gaiassi, A., Rocchio, I., Rovelli, G., Pomarico, R., Sandrone, G., et al. (2024). Mechanistic and Structural Insights on Difluoromethyl-1,3,4-Oxadiazole Inhibitors of HDAC6. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 25(11), 1-12 [10.3390/ijms25115885].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/480760
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