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

0520948 - BTÚ 2020 RIV US eng J - Journal Article
Kozikowski, A. P. - Shen, S. - Pardo, M. - Tayares, M. T. - Szarics, D. - Benoy, V. - Zimprich, Ch. A. - Kutil, Zsofia - Zhang, G. - Bařinka, Cyril - Robers, M. B. - Van den Bosch, L. - Eubanks, J. H. - Jope, R. S.
Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome.
ACS Chemical Neuroscience. Roč. 10, č. 3 (2019), s. 1679-1695. ISSN 1948-7193. E-ISSN 1948-7193
R&D Projects: GA ČR GA15-19640S; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : fmr1 knockout mice * mental-retardation protein * tubulin acetylation * metabotropic glutamate * negative regulator
OECD category: Biochemistry and molecular biology
Impact factor: 4.486, year: 2019
Method of publishing: Open access
https://pubs.acs.org/doi/10.1021/acschemneuro.8b00600

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, Fmr1-1- 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 alpha-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates alpha-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated alpha-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.
Permanent Link: http://hdl.handle.net/11104/0305622