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

0550576 - BTÚ 2022 RIV US eng J - Journal Article
Shen, S. - Picci, C. - Ustinova, Kseniya - Benoy, V. - Kutil, Zsofia - Zhang, G. - Tavares, M. T. - Pavlíček, Jiří - Zimprich, Ch. A. - Robers, M. B. - Van den Bosch, L. - Bařinka, Cyril - Langley, B. - Kozikowski, A. P.
Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model.
Journal of Medicinal Chemistry. Roč. 64, č. 8 (2021), s. 4810-4840. ISSN 0022-2623. E-ISSN 1520-4804
Institutional support: RVO:86652036
Keywords : hdac6 inhibitors * acetylation * disease * neuropathy
OECD category: Medicinal chemistry
Impact factor: 8.039, year: 2021
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02210

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 alpha-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.
Permanent Link: http://hdl.handle.net/11104/0329546