Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• ACS chemical neuroscience, 2019-03, Vol.10 (3), p.1679-1695

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.