title: A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors.
abstract: The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.|Laboratory for Cheminformatics and Molecular Modeling, Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto, 8, 06123 Perugia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Deschamps
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Giuseppe Marco
authors.initials: GM
authors.lastname: Randazzo
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Petit
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Carolina
authors.initials: C
authors.lastname: Dos Santos Passos
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Simões-Pires
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.|Département de Biochimie, Université de Montréal, H3C 3J7 Montréal, Québec, Canada.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
mesh_terms: D000107:Acetylation; D001812:Blood-Brain Barrier / Q000187:drug effects; D019295:Computational Biology; D062126:Databases, Chemical; D000073864:Histone Deacetylase 6 / Q000737:chemistry / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020033:Protein Isoforms; D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6