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

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 SteegbornJ. Lawrence Marsh, Donald C. Lo, Leslie M. Thompson, Aleksey G. Kazantsev

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    36 Citations (Scopus)
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    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.

    Original languageEnglish
    Pages (from-to)849-861
    Number of pages13
    JournalCell Chemical Biology
    Volume23
    Issue number7
    Early online date14 Jul 2016
    DOIs
    Publication statusPublished - 21 Jul 2016

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