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.
N1 - Funding Information:
*E-mail: akozikowski@starwisetrx.com. Phone: 773-793-5866. ORCID Sida Shen: 0000-0002-0295-2545 Maurício T. Tavares: 0000-0002-4400-7787 Guiping Zhang: 0000-0001-9818-4773 Cyril Barǐ nka: 0000-0003-2751-3060 Present Addresses ◆S.S.: Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois 60208, United States. ¶M.P.: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States. +M.T.T: Faculty of Pharmaceutical Sciences, Department of Pharmacy, University of Saõ Paulo, Saõ Paulo, Brazil. Author Contributions ○S.S. and M.P. contributed equally to this paper. StarWise Therapeutics LLC: A.P.K. conceived the original idea, initiated the project, and oversaw all the experimental design and data analysis. University of Illinois at Chicago: S.S. designed and synthesized compounds, oversaw all the experimental design, analyzed data, and wrote the manuscript with assistance from the other authors; M.T.T. synthesized compounds, performed the docking studies, and assisted in the preparation of the manuscript; G.Z. synthesized some of the reported compounds. University of Miami: M.P. designed and performed the in vivo FXS mice model studies and assisted in the preparation of the manuscript, R.S.J. oversaw the experimental design and data analyses of animal studies. University Health Network: D.S. designed and performed the dose−response tubulin acetylation studies in HEK293 cells and assisted in the preparation of the manuscript, and J.H.E. oversaw the experimental design and data analyses of the in vitro tubulin acetylation study. Leuven Research Institute for Neuroscience and Disease: V.B. designed and performed the tubulin/histone acetylation studies in N2a and assisted in the preparation of the manuscript; L.V.D.B. oversaw the experimental design and data analyses of the in vitro tubulin acetylation study. Promega Corporation: C.A.Z. designed and performed the cellular HDAC target engagement assay; M.B.R. oversaw the experimental design and data analyses of target engagement study and assisted in the preparation of the manuscript. Institute of Biotechnology of the Czech Academy of Sciences: Z.K. performed and confirmed the HDAC6 and HDAC11 data for SW-100. C.B. oversaw the experimental design and data analyses of HDAC enzyme studies. Funding This work was supported by grants from the NIH (NS079183, to A.P.K. and L.V.D.B) and the CIHR (PJT-153015, to J.H.E), and a NARSAD Distinguished Investigator Grant to R.S.J. from the Brain & Behavior Research Foundation. This work was also in part supported by the Czech Science Foundation (15-19640S), the CAS (RVO: 86652036), and the project “BIOCEV” (CZ.1.05/1.1.00/02.0109) from the ERDF. Notes The authors declare the following competing financial interest(s): A.P.K. is the owner of StarWise Therapeutics LLC and thus declares potential financial interests as does G.Z. who is employed by StarWise Therapeutics.
PY - 2019/3/20
Y1 - 2019/3/20
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 (IC 50 = 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 (IC 50 = 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 - Ames negative
KW - Phenylhydroxamate
KW - acetylated α-tubulin
KW - memory and learning impairments
KW - permeability
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U2 - 10.1021/acschemneuro.8b00600
DO - 10.1021/acschemneuro.8b00600
M3 - Article
C2 - 30511829
AN - SCOPUS:85058888450
VL - 10
SP - 1679
EP - 1695
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 3
ER -