SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.
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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Related Subject Headings
- Thiazoles
- Structure-Activity Relationship
- Sirtuin 2
- Rats
- Neuroprotective Agents
- NF-E2-Related Factor 2
- Huntington Disease
- Drosophila
- Dose-Response Relationship, Drug
- Disease Models, Animal
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Thiazoles
- Structure-Activity Relationship
- Sirtuin 2
- Rats
- Neuroprotective Agents
- NF-E2-Related Factor 2
- Huntington Disease
- Drosophila
- Dose-Response Relationship, Drug
- Disease Models, Animal