SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models
journal contribution
posted on 2019-04-04, 12:28 authored 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 KazantsevThere 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.
Funding
This work was supported by grants from the NIHU01-NS066912, R01NS04528, NIH NS078370, NIH NS080514, and NIGMS grant GM080356, the Biotechnology and Biological Sciences Research Council (BB/J007498/1, BB/L01923X/1), Alzheimer Forschung Initiative (grant 14834 to C.S.) and Cancer Research UK (C20953/A18644). We also acknowledge support from the RJG foundation to L.Q and A.G.K and from the American Heart Association to R.G.L. This work was made possible in part by the availability of the Optical Biology Shared Resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine. We thank Michael McMahon (University of Dundee) for plasmids encoding wild-type Keap1.
History
Citation
Cell Chem Biol, 2016, 23 (7), pp. 849-861Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Neuroscience, Psychology and BehaviourVersion
- AM (Accepted Manuscript)
Published in
Cell Chem BiolPublisher
Elseviereissn
2451-9456Acceptance date
2016-05-17Copyright date
2016Available date
2019-04-04Publisher DOI
Publisher version
https://www.sciencedirect.com/science/article/pii/S2451945616301957?via=ihubLanguage
enAdministrator link
Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC