| Autor: |
Kozikowski AP; StarWise Therapeutics LLC , Madison , Wisconsin 53719 , United States., Shen S; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States., Pardo M; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine , University of Miami , Miami , Florida 33136 , United States., Tavares MT; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States., Szarics D; Division of Genetics and Development, Krembil Research Institute , University Health Network , Toronto , Ontario M5G 2C4 , Canada., Benoy V; Laboratory of Neurobiology, Center for Brain & Disease (VIB) and Leuven Brain Institute (LBI) , KU Leuven , B-3000 Leuven , Belgium., Zimprich CA; Promega Corporation , Madison , Wisconsin 53711 , United States., Kutil Z; Laboratory of Structural Biology , Institute of Biotechnology of the Czech Academy of Sciences , Prumyslova 595 , 252 50 Vestec , Czech Republic., Zhang G; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , University of Illinois at Chicago , Chicago , Illinois 60612 , United States., Bařinka C; Laboratory of Structural Biology , Institute of Biotechnology of the Czech Academy of Sciences , Prumyslova 595 , 252 50 Vestec , Czech Republic., Robers MB; Promega Corporation , Madison , Wisconsin 53711 , United States., Van Den Bosch L; Laboratory of Neurobiology, Center for Brain & Disease (VIB) and Leuven Brain Institute (LBI) , KU Leuven , B-3000 Leuven , Belgium., Eubanks JH; Division of Genetics and Development, Krembil Research Institute , University Health Network , Toronto , Ontario M5G 2C4 , Canada., Jope RS; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine , University of Miami , Miami , Florida 33136 , United States. |
| Abstrakt: |
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. |
