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SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models
- Quinti, Luisa;
- Casale, Malcolm;
- Moniot, Sébastien;
- Pais, Teresa F;
- Van Kanegan, Michael J;
- Kaltenbach, Linda S;
- Pallos, Judit;
- Lim, Ryan G;
- Naidu, Sharadha Dayalan;
- Runne, Heike;
- Meisel, Lisa;
- Rauf, Nazifa Abdul;
- Leyfer, Dmitriy;
- Maxwell, Michele M;
- Saiah, Eddine;
- Landers, John E;
- Luthi-Carter, Ruth;
- Abagyan, Ruben;
- Dinkova-Kostova, Albena T;
- Steegborn, Clemens;
- Marsh, J Lawrence;
- Lo, Donald C;
- Thompson, Leslie M;
- Kazantsev, Aleksey G
- et al.
Published Web Location
https://doi.org/10.1016/j.chembiol.2016.05.015Abstract
There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders.
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