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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Chemical Neuroscience

ISSN

1948-7193

e-ISSN

—

Svazek periodika

10

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

17

Strana od-do

1679-1695

Kód UT WoS článku

000462259900073

EID výsledku v databázi Scopus

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