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Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome
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SYSNO ASEP 0520948 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome Author(s) Kozikowski, A. P. (US)
Shen, S. (US)
Pardo, M. (US)
Tayares, M. T. (US)
Szarics, D. (CA)
Benoy, V. (BE)
Zimprich, Ch. A. (US)
Kutil, Zsofia (BTO-N) RID, ORCID
Zhang, G. (US)
Bařinka, Cyril (BTO-N) RID, ORCID
Robers, M. B. (US)
Van den Bosch, L. (BE)
Eubanks, J. H. (CA)
Jope, R. S. (US)Number of authors 14 Source Title ACS Chemical Neuroscience. - : American Chemical Society - ISSN 1948-7193
Roč. 10, č. 3 (2019), s. 1679-1695Number of pages 17 s. Language eng - English Country US - United States Keywords fmr1 knockout mice ; mental-retardation protein ; tubulin acetylation ; metabotropic glutamate ; negative regulator Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects GA15-19640S GA ČR - Czech Science Foundation (CSF) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support BTO-N - RVO:86652036 UT WOS 000462259900073 DOI 10.1021/acschemneuro.8b00600 Annotation 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. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2020 Electronic address https://pubs.acs.org/doi/10.1021/acschemneuro.8b00600
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