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SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

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journal contribution
posted 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.

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. 849-861

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Neuroscience, Psychology and Behaviour

Version

AM (Accepted Manuscript)

Published in

Cell Chem Biol

Publisher

Elsevier

eissn

2451-9456

Acceptance date

17/05/2016

Copyright date

2016

Available date

04/04/2019

Publisher version

https://www.sciencedirect.com/science/article/pii/S2451945616301957?via=ihub

Language

en