Quinti, L., Casale, M., Moniot, S., Pais, T.F., Van Kanegan, M.J., Kaltenbach, L.S., Pallos, J., Lim, R.G., Naidu, S.D., Runne, H., Meisel, L., Rauf, N.A., Leyfer, D., Maxwell, M.M., Saiah, E., Landers, J.E., Luthi-Carter, R., Abagyan, R., Dinkova-Kostova, A.T., Steegborn, C., Marsh, J.L., Lo, D.C., Thompson, L.M., Kazantsev, A.G. (2016). SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.  Cell Chem. Biol. 23(7): 849--861.

FBrf0232888

Research paper

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.