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

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 select...

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Published in:International journal of molecular sciences 2024-06, Vol.25 (11), p.5885
Main Authors: Cellupica, Edoardo, Gaiassi, Aureliano, Rocchio, Ilaria, Rovelli, Grazia, Pomarico, Roberta, Sandrone, Giovanni, Caprini, Gianluca, Cordella, Paola, Cukier, Cyprian, Fossati, Gianluca, Marchini, Mattia, Bebel, Aleksandra, Airoldi, Cristina, Palmioli, Alessandro, Stevenazzi, Andrea, Steinkühler, Christian, Vergani, Barbara
Format: Article
Language:English
Subjects:
Chemical bonds
Chromatography
Crystallography, X-Ray
Enzyme inhibitors
Enzyme kinetics
Histone Deacetylase 6 - antagonists & inhibitors
Histone Deacetylase 6 - chemistry
Histone Deacetylase 6 - metabolism
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - pharmacology
Humans
Hydrolysis
Investigations
Kinetics
Liquid chromatography
Mass spectrometry
Medical research
Medicine, Experimental
Models, Molecular
NMR
Nuclear magnetic resonance
Nuclear magnetic resonance spectroscopy
Oxadiazoles - chemistry
Oxadiazoles - pharmacology
Polyamines
Protein Binding
Proteins
Structure-Activity Relationship
Zinc
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25115885