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.

Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy University of Illinois at Chicago Chicago Illinois 60612 United States

Department of Psychiatry and Behavioral Sciences Miller School of Medicine University of Miami Miami Florida 33136 United States

Division of Genetics and Development Krembil Research Institute University Health Network Toronto Ontario M5G 2C4 Canada

Laboratory of Neurobiology Center for Brain and Disease KU Leuven B 3000 Leuven Belgium

Laboratory of Structural Biology Institute of Biotechnology of the Czech Academy of Sciences Prumyslova 595 252 50 Vestec Czech Republic

Promega Corporation Madison Wisconsin 53711 United States

StarWise Therapeutics LLC Madison Wisconsin 53719 United States

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