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  • SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.

SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.

Cell chemical biology (2016-07-19)
Luisa Quinti, Malcolm Casale, Sébastien Moniot, Teresa F Pais, Michael J Van Kanegan, Linda S Kaltenbach, Judit Pallos, Ryan G Lim, Sharadha Dayalan Naidu, Heike Runne, Lisa Meisel, Nazifa Abdul Rauf, Dmitriy Leyfer, Michele M Maxwell, Eddine Saiah, John E Landers, Ruth Luthi-Carter, Ruben Abagyan, Albena T Dinkova-Kostova, Clemens Steegborn, J Lawrence Marsh, Donald C Lo, Leslie M Thompson, Aleksey G Kazantsev
PMID27427231
ABSTRACT

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.