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

Alan P. Kozikowski, Sida Shen, Marta Pardo, Maurício T. Tavares, Dora Szarics, Veronick Benoy, Chad A. Zimprich, Zsófia Kutil, Guiping Zhang, Cyril Bařinka, Matthew B. Robers, Ludo Van Den Bosch, James H. Eubanks, Richard S Jope

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 languageEnglish (US)
JournalACS Chemical Neuroscience
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Fragile X Syndrome
Histone Deacetylase Inhibitors
Histone Deacetylases
Brain
Tubulin
Learning
Data storage equipment
Acetylation
Aptitude
Penetrance
Rare Diseases
Histones
Inhibitory Concentration 50
Hippocampus
Protein Isoforms
Up-Regulation
Pharmacology
Molecules
Therapeutics
Inhibition (Psychology)

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 journalArticle

Kozikowski, AP, Shen, S, Pardo, M, Tavares, MT, Szarics, D, Benoy, V, Zimprich, CA, Kutil, Z, Zhang, G, Bařinka, C, Robers, MB, Van Den Bosch, L, Eubanks, JH & Jope, RS 2018, 'Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome', ACS Chemical Neuroscience. https://doi.org/10.1021/acschemneuro.8b00600
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. / Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome. In: ACS Chemical Neuroscience. 2018.
@article{d768b10196674f64b6b58890a5c3908e,
title = "Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome",
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.",
keywords = "acetylated α-tubulin, Ames negative, memory and learning impairments, permeability, Phenylhydroxamate",
author = "Kozikowski, {Alan P.} and Sida Shen and Marta Pardo and Tavares, {Maur{\'i}cio T.} and Dora Szarics and Veronick Benoy and Zimprich, {Chad A.} and Zs{\'o}fia Kutil and Guiping Zhang and Cyril Bařinka and Robers, {Matthew B.} and {Van Den Bosch}, Ludo and Eubanks, {James H.} and Jope, {Richard S}",
year = "2018",
month = "1",
day = "1",
doi = "10.1021/acschemneuro.8b00600",
language = "English (US)",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",

}

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 -