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

Alan P. Kozikowski, Sida Shen, Marta Pardo, Maurício T. Tavares, Dora Szarics, Veronick Benoy, Chad A. Zimprich, Zsófia Kutil, Guiping Zhang, Cyril Bařinka, Matthew B. Robers, Ludo Van Den Bosch, James H. Eubanks, Richard S. Jope

Research output: Contribution to journalArticle

11 Scopus citations

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 (IC 50 = 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.

Original languageEnglish (US)
Pages (from-to)1679-1695
Number of pages17
JournalACS Chemical Neuroscience
Volume10
Issue number3
DOIs
StatePublished - Mar 20 2019

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Kozikowski, A. P., Shen, S., Pardo, M., Tavares, M. T., Szarics, D., Benoy, V., Zimprich, C. A., Kutil, Z., Zhang, G., Bařinka, C., Robers, M. B., Van Den Bosch, L., Eubanks, J. H., & Jope, R. S. (2019). Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome. ACS Chemical Neuroscience, 10(3), 1679-1695. https://doi.org/10.1021/acschemneuro.8b00600