title: Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease.
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.
authors.affiliation: Drug Discovery Program, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Sida
authors.initials: S
authors.lastname: Shen
authors.affiliation: Laboratory of Neurobiology, Vesalius Research Center (VIB) and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven , O&N4 Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Veronick
authors.initials: V
authors.lastname: Benoy
authors.affiliation: Drug Discovery Program, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Bergman
authors.affiliation: Drug Discovery Program, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kalin
authors.affiliation: Drug Discovery Program, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Mariana
authors.initials: M
authors.lastname: Frojuello
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano , Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.affiliation: Laboratory of Neurobiology, Vesalius Research Center (VIB) and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven , O&N4 Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Wanda
authors.initials: W
authors.lastname: Haeck
authors.affiliation: Laboratory of Neurobiology, Vesalius Research Center (VIB) and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven , O&N4 Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.affiliation: Drug Discovery Program, University of Illinois at Chicago , 833 S. Wood St., Chicago, Illinois 60612, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy* / Q000201:enzymology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D007376:Interleukin-2; D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Charcot−Marie−Tooth disease; Selective histone deacetylase 6 inhibitor; hydroxamic acid; mitochondrial axonal transport; mutant HSPB1-expressing DRG neurons; tubulin acetylation