Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot–Marie–Tooth Type 2A Mouse Model
- Sida ShenSida ShenDepartment of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United StatesMore by Sida Shen
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- Cristina PicciCristina PicciSchool of Health, The University of Waikato, Private Bag 3105, Hamilton 3240, New ZealandMore by Cristina Picci
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- Kseniya UstinovaKseniya UstinovaInstitute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech RepublicMore by Kseniya Ustinova
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- Veronick BenoyVeronick BenoyLaboratory of Neurobiology, Center for Brain & Disease (VIB) and Leuven Brain Institute (LBI), KU Leuven, B-3000 Leuven, BelgiumMore by Veronick Benoy
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- Zsófia KutilZsófia KutilInstitute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech RepublicMore by Zsófia Kutil
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- Guiping ZhangGuiping ZhangDepartment of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United StatesMore by Guiping Zhang
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- Maurício T. TavaresMaurício T. TavaresDepartment of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United StatesMore by Maurício T. Tavares
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- Jiří PavlíčekJiří PavlíčekInstitute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech RepublicMore by Jiří Pavlíček
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- Chad A. ZimprichChad A. ZimprichPromega Corporation, Madison, Wisconsin 53711, United StatesMore by Chad A. Zimprich
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- Matthew B. RobersMatthew B. RobersPromega Corporation, Madison, Wisconsin 53711, United StatesMore by Matthew B. Robers
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- Ludo Van Den BoschLudo Van Den BoschLaboratory of Neurobiology, Center for Brain & Disease (VIB) and Leuven Brain Institute (LBI), KU Leuven, B-3000 Leuven, BelgiumMore by Ludo Van Den Bosch
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- Cyril Bařinka*Cyril Bařinka*Email: [email protected]. Phone: +420-325-873-777.Institute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech RepublicMore by Cyril Bařinka
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- Brett Langley*Brett Langley*Email: [email protected]. Phone: +64-7-838-4060.School of Health, The University of Waikato, Private Bag 3105, Hamilton 3240, New ZealandMore by Brett Langley
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- Alan P. Kozikowski*Alan P. Kozikowski*Email: [email protected]. Phone: +1-773-793-5866.Bright Minds Biosciences, Toronto, ON M5H 3V9, CanadaMore by Alan P. Kozikowski
Abstract
Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot–Marie–Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.
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This article is cited by 3 publications.
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- Giovanni Sandrone, Cyprian D. Cukier, Karol Zrubek, Mattia Marchini, Barbara Vergani, Gianluca Caprini, Gianluca Fossati, Christian Steinkühler, Andrea Stevenazzi. Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors. ACS Medicinal Chemistry Letters 2021, 12 (11) , 1810-1817. https://doi.org/10.1021/acsmedchemlett.1c00425