title: Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot-Marie-Tooth Disease.
abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500. The degeneration of motor and sensory nerve axons leads to motor and sensory symptoms that progress over time and have an important impact on the daily life of these patients. Currently, there is no curative treatment available. Recently, we identified histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, as a potential therapeutic target in axonal CMT (CMT2). Pharmacological inhibition of the deacetylating function of HDAC6 reversed the motor and sensory deficits in a mouse model for mutant "small heat shock protein B1" (HSPB1)-induced CMT2 at the behavioral and electrophysiological level. In order to translate this potential therapeutic strategy into a clinical application, small drug-like molecules that are potent and selective HDAC6 inhibitors are essential. To screen for these, we developed a method that consisted of 3 distinct phases and that was based on the pathological findings in the mutant HSPB1-induced CMT2 mouse model. Three different inhibitors (ACY-738, ACY-775, and ACY-1215) were tested and demonstrated to be both potent and selective HDAC6 inhibitors. Moreover, these inhibitors increased the innervation of the neuromuscular junctions in the gastrocnemius muscle and improved the motor and sensory nerve conduction, confirming that HDAC6 inhibition is a potential therapeutic strategy in CMT2. Furthermore, ACY-1215 is an interesting lead molecule as it is currently tested in clinical trials for cancer. Taken together, these results may speed up the translation of pharmacological inhibition of HDAC6 into a therapy against CMT2.
authors.affiliation: KU Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, B-3000, Leuven, Belgium.|VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, B-3000, Leuven, Belgium.
authors.forename: Veronick
authors.identifier: http://orcid.org/0000-0001-5551-5624
authors.initials: V
authors.lastname: Benoy
authors.affiliation: Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, B-3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Vanden Berghe
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jarpe
authors.affiliation: KU Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, B-3000, Leuven, Belgium.|VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, B-3000, Leuven, Belgium.|Department of Neurology, University Hospitals Leuven, B-3000, Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.affiliation: KU Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, B-3000, Leuven, Belgium.|Department of Neurology, University Hospitals Leuven, B-3000, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: KU Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, B-3000, Leuven, Belgium. ludo.vandenbosch@vib-kuleuven.be.|VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, B-3000, Leuven, Belgium. ludo.vandenbosch@vib-kuleuven.be.
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy* / Q000201:enzymology*; D004353:Drug Evaluation, Preclinical; D005727:Ganglia, Spinal / Q000187:drug effects; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation; D009469:Neuromuscular Junction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: C583721:2-((1-(3-fluorophenyl)cyclohexyl)amino)-N-hydroxypyrimidine-5-carboxamide; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C583720:N-hydroxy-2-(1-phenylcycloproylamino)pyrimidine-5-carboxamide; D011743:Pyrimidines; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6
keywords: Acetylated α-tubulin; Charcot–Marie–Tooth disease; Compound screening; HSPB1; Histone deacetylase 6; Mitochondria