TY - JOUR
T1 - Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease
AU - Shen, Sida
AU - Benoy, Veronick
AU - Bergman, Joel A.
AU - Kalin, Jay H.
AU - Frojuello, Mariana
AU - Vistoli, Giulio
AU - Haeck, Wanda
AU - Van Den Bosch, Ludo
AU - Kozikowski, Alan P.
N1 - Funding Information:
The authors gratefully acknowledge financial support from the NIH (NS079183, A.P.K. and L.V.D.B). V.B., W.H., and L.V.D.B. are supported by grants from the Fund for Scientific Research Flanders (FWO-Vlaanderen), the University of Leuven, the Belgian government (Interuniversity Attraction Poles of the Belgian Federal Science Policy Office), the Association Belge contre les Maladies neuro-Musculaires (ABMM), the ALS Association (ALSA), the ALS Therapy Alliance, the Muscular Dystrophy Association (MDA), and the European Community''s Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867). V.B. is supported by the Agency for Innovation by Science and Technology in Flanders (IWTVlaanderen).The authors also thank Dr. Werner Tueckmantel for reviewing the Article and providing comments.
Publisher Copyright:
© 2015 American Chemical Society.
PY - 2016/2/17
Y1 - 2016/2/17
N2 - 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.
AB - 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.
KW - Charcot-Marie-Tooth disease
KW - Selective histone deacetylase 6 inhibitor
KW - hydroxamic acid
KW - mitochondrial axonal transport
KW - mutant HSPB1-expressing DRG neurons
KW - tubulin acetylation
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U2 - 10.1021/acschemneuro.5b00286
DO - 10.1021/acschemneuro.5b00286
M3 - Article
C2 - 26599234
AN - SCOPUS:84959327832
SN - 1948-7193
VL - 7
SP - 240
EP - 258
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 2
ER -