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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F19%3A00520948" target="_blank" >RIV/86652036:_____/19:00520948 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acschemneuro.8b00600" target="_blank" >https://pubs.acs.org/doi/10.1021/acschemneuro.8b00600</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acschemneuro.8b00600" target="_blank" >10.1021/acschemneuro.8b00600</a>

Result language
angličtina
Original language name
Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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