2381/43706 L Quinti L Quinti M Casale M Casale S Moniot S Moniot TF Pais TF Pais MJ Van Kanegan MJ Van Kanegan LS Kaltenbach LS Kaltenbach J Pallos J Pallos RG Lim RG Lim SD Naidu SD Naidu H Runne H Runne L Meisel L Meisel NA Rauf NA Rauf D Leyfer D Leyfer MM Maxwell MM Maxwell E Saiah E Saiah JE Landers JE Landers R Luthi-Carter R Luthi-Carter R Abagyan R Abagyan AT Dinkova-Kostova AT Dinkova-Kostova C Steegborn C Steegborn JL Marsh JL Marsh DC Lo DC Lo LM Thompson LM Thompson AG Kazantsev AG Kazantsev SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models University of Leicester 2019 Animals Cell Line Disease Models, Animal Dose-Response Relationship, Drug Drosophila Huntington Disease NF-E2-Related Factor 2 Neuroprotective Agents Rats Sirtuin 2 Structure-Activity Relationship Thiazoles 2019-04-04 12:28:59 Journal contribution https://figshare.le.ac.uk/articles/journal_contribution/SIRT2-_and_NRF2-Targeting_Thiazole-Containing_Compound_with_Therapeutic_Activity_in_Huntington_s_Disease_Models/10213388 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.