Abstract
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.
| Original language | English (US) |
|---|---|
| Journal | ACS Chemical Neuroscience |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- acetylated α-tubulin
- Ames negative
- memory and learning impairments
- permeability
- Phenylhydroxamate
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Cognitive Neuroscience
- Cell Biology
Cite this
Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome. / 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.
In: ACS Chemical Neuroscience, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome
AU - Kozikowski, Alan P.
AU - Shen, Sida
AU - Pardo, Marta
AU - Tavares, Maurício T.
AU - Szarics, Dora
AU - Benoy, Veronick
AU - Zimprich, Chad A.
AU - Kutil, Zsófia
AU - Zhang, Guiping
AU - Bařinka, Cyril
AU - Robers, Matthew B.
AU - Van Den Bosch, Ludo
AU - Eubanks, James H.
AU - Jope, Richard S
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - acetylated α-tubulin
KW - Ames negative
KW - memory and learning impairments
KW - permeability
KW - Phenylhydroxamate
UR - http://www.scopus.com/inward/record.url?scp=85058888450&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058888450&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.8b00600
DO - 10.1021/acschemneuro.8b00600
M3 - Article
C2 - 30511829
AN - SCOPUS:85058888450
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
ER -