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

Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy University of Illinois at Chicago Chicago Illinois 60612 United States

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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