Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease
Articolo
Data di Pubblicazione:
2016
Citazione:
Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease / S. Shen, V. Benoy, J.A. Bergman, J.H. Kalin, M. Frojuello, G. Vistoli, W. Haeck, L. Van Den Bosch, A.P. Kozikowski. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 7:2(2016 Feb 17), pp. 240-258. [10.1021/acschemneuro.5b00286]
Abstract:
Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Charcot-Marie-Tooth disease; hydroxamic acid; mitochondrial axonal transport; mutant hspb1-expressing drg neurons; selective histone deacetylase 6 inhibitor; tubulin acetylation; biochemistry; cell biology; physiology; cognitive neuroscience
Elenco autori:
S. Shen, V. Benoy, J.A. Bergman, J.H. Kalin, M. Frojuello, G. Vistoli, W. Haeck, L. Van Den Bosch, A.P. Kozikowski
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