Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
R01 NS079183
NINDS NIH HHS - United States
R43 HD093464
NICHD NIH HHS - United States
R41 AG058283
NIA NIH HHS - United States
- MeSH
- Acetylation MeSH
- Benzamides chemistry metabolism MeSH
- Charcot-Marie-Tooth Disease drug therapy metabolism pathology MeSH
- Quinolines chemistry metabolism therapeutic use MeSH
- Phenotype MeSH
- Histone Deacetylase 6 antagonists & inhibitors metabolism MeSH
- Histone Deacetylase Inhibitors chemistry metabolism therapeutic use MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Half-Life MeSH
- Protein Isoforms antagonists & inhibitors metabolism MeSH
- Molecular Docking Simulation MeSH
- Tubulin metabolism MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- 1,2,3,4-tetrahydroquinoline MeSH Browser
- Benzamides MeSH
- Quinolines MeSH
- Histone Deacetylase 6 MeSH
- Histone Deacetylase Inhibitors MeSH
- Protein Isoforms MeSH
- SW-100 MeSH Browser
- Tubulin MeSH
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.
Bright Minds Biosciences Toronto ON M5H 3V9 Canada
Institute of Biotechnology of the Czech Academy of Sciences 252 50 Vestec Czech Republic
Laboratory of Neurobiology Center for Brain and Disease KU Leuven B 3000 Leuven Belgium
Promega Corporation Madison Wisconsin 53711 United States
School of Health The University of Waikato Private Bag 3105 Hamilton 3240 New Zealand
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