2. Academic Validation
  3. Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome

  • ACS Chem Neurosci. 2019 Mar 20;10(3):1679-1695. doi: 10.1021/acschemneuro.8b00600.
Alan P Kozikowski 1,  Sida Shen 2,  Marta Pardo 3,  Maurício T Tavares 2,  Dora Szarics 4,  Veronick Benoy 5,  Chad A Zimprich 6,  Zsófia Kutil 7,  Guiping Zhang 2,  Cyril Bařinka 7,  Matthew B Robers 6,  Ludo Van Den Bosch 5,  James H Eubanks 4,  Richard S Jope 3
Affiliations

Affiliations

  • 1 StarWise Therapeutics LLC , Madison , Wisconsin 53719 , United States.
  • 2 Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States.
  • 3 Department of Psychiatry and Behavioral Sciences, Miller School of Medicine , University of Miami , Miami , Florida 33136 , United States.
  • 4 Division of Genetics and Development, Krembil Research Institute , University Health Network , Toronto , Ontario M5G 2C4 , Canada.
  • 5 Laboratory of Neurobiology, Center for Brain & Disease (VIB) and Leuven Brain Institute (LBI) , KU Leuven , B-3000 Leuven , Belgium.
  • 6 Promega Corporation , Madison , Wisconsin 53711 , United States.
  • 7 Laboratory of Structural Biology , Institute of Biotechnology of the Czech Academy of Sciences , Prumyslova 595 , 252 50 Vestec , Czech Republic.
PMID: 30511829 DOI: 10.1021/acschemneuro.8b00600
Abstract

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1-/- mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the α-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates α-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated α-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.

Keywords

Ames negative; Phenylhydroxamate; acetylated α-tubulin; memory and learning impairments; permeability.

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