| Autor: |
Shen S; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States., Picci C; School of Health, The University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand., Ustinova K; Institute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech Republic., Benoy V; Laboratory of Neurobiology, Center for Brain & Disease (VIB) and Leuven Brain Institute (LBI), KU Leuven, B-3000 Leuven, Belgium., Kutil Z; Institute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech Republic., Zhang G; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States., Tavares MT; Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States., Pavlíček J; Institute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech Republic., Zimprich CA; Promega Corporation, Madison, Wisconsin 53711, United States., Robers MB; Promega Corporation, Madison, Wisconsin 53711, United States., Van Den Bosch L; Laboratory of Neurobiology, Center for Brain & Disease (VIB) and Leuven Brain Institute (LBI), KU Leuven, B-3000 Leuven, Belgium., Bařinka C; Institute of Biotechnology of the Czech Academy of Sciences, 252 50 Vestec, Czech Republic., Langley B; School of Health, The University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand., Kozikowski AP; Bright Minds Biosciences, Toronto, ON M5H 3V9, Canada. |
| Abstrakt: |
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. |
