SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models
journal contributionposted on 04.04.2019, 12:28 by L Quinti, M Casale, S Moniot, TF Pais, MJ Van Kanegan, LS Kaltenbach, J Pallos, RG Lim, SD Naidu, H Runne, L Meisel, NA Rauf, D Leyfer, MM Maxwell, E Saiah, JE Landers, R Luthi-Carter, R Abagyan, AT Dinkova-Kostova, C Steegborn, JL Marsh, DC Lo, LM Thompson, AG Kazantsev
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.