Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model.

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.

• Authors: Sida Shen, Cristina Picci, Kseniya Ustinova, Veronick Benoy, Zsófia Kutil, Guiping Zhang, Maurício T Tavares, Jiří Pavlíček, Chad A Zimprich, Matthew B Robers, Ludo Van Den Bosch, Cyril Bařinka, Brett Langley, Alan P Kozikowski
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 8 Pg. 4810-4840 (04 22 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33830764 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• Protein Isoforms
• Quinolines
• SW-100
• Tubulin
• 1,2,3,4-tetrahydroquinoline
• Histone Deacetylase 6

Topics

• Acetylation
• Animals
• Benzamides (chemistry, metabolism)
• Binding Sites
• Charcot-Marie-Tooth Disease (drug therapy, metabolism, pathology)
• Crystallography, X-Ray
• Disease Models, Animal
• Half-Life
• Histone Deacetylase 6 (antagonists & inhibitors, metabolism)
• Histone Deacetylase Inhibitors (chemistry, metabolism, therapeutic use)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Docking Simulation
• Phenotype
• Protein Isoforms (antagonists & inhibitors, metabolism)
• Quinolines (chemistry, metabolism, therapeutic use)
• Structure-Activity Relationship
• Tubulin (metabolism)