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

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.

• Authors: 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
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 10 Issue 3 Pg. 1679-1695 (03 20 2019) ISSN: 1948-7193 [Electronic] United States
• PMID: 30511829 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• Quinolines
• SW-100
• Histone Deacetylase 6

Topics

• Animals
• Benzamides (pharmacology)
• Cognition (drug effects)
• Disease Models, Animal
• Fragile X Syndrome (enzymology, physiopathology)
• Hippocampus (drug effects, metabolism)
• Histone Deacetylase 6 (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (pharmacology)
• Learning (drug effects)
• Memory (drug effects)
• Mice
• Protein Processing, Post-Translational (drug effects)
• Quinolines (pharmacology)