| Literature DB >> 27427231 |
Luisa Quinti1, Malcolm Casale2, Sébastien Moniot3, Teresa F Pais4, Michael J Van Kanegan5, Linda S Kaltenbach5, Judit Pallos6, Ryan G Lim7, Sharadha Dayalan Naidu8, Heike Runne9, Lisa Meisel3, Nazifa Abdul Rauf1, Dmitriy Leyfer1, Michele M Maxwell1, Eddine Saiah10, John E Landers11, Ruth Luthi-Carter9, Ruben Abagyan12, Albena T Dinkova-Kostova13, Clemens Steegborn3, J Lawrence Marsh6, Donald C Lo5, Leslie M Thompson14, Aleksey G Kazantsev15.
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.Entities:
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Year: 2016 PMID： 27427231 DOI： 10.1016/j.chembiol.2016.05.015
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 8.116