Download MendeleyTetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model.
Shen, S., Picci, C., Ustinova, K., Benoy, V., Kutil, Z., Zhang, G., Tavares, M.T., Pavlicek, J., Zimprich, C.A., Robers, M.B., Van Den Bosch, L., Barinka, C., Langley, B., Kozikowski, A.P.(2021) J Med Chem 64: 4810-4840
- PubMed: 33830764
- DOI: https://doi.org/10.1021/acs.jmedchem.0c02210
- Primary Citation of Related Structures:
6ZW1 - PubMed 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 MFN 2. Taken together, these results bode well for the further development of SW-101 ( 1s ) as a disease-modifying HDAC6i.
Organizational Affiliation:
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
