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SIRT2- And NRF2-Targeting Thiazole-Containing Compound With Therapeutic Activity in Huntington's Disease Models

SIRT2- And NRF2-Targeting Thiazole-Containing Compound With Therapeutic Activity in Huntington's Disease Models

Luisa Quinti, Malcolm Casale, Sébastien Moniot, Teresa F Pais, Michael J Van Kanegan, Linda S Kaltenbach, Judit Pallos, Ryan G Lim, Sharadha Dayalan Naidu, Heike Runne, Lisa Meisel, Nazifa Abdul Rauf, Dmitriy Leyfer, etc.

Cell Chem Biol. 2016 Jul 21;23(7):849-861.

PMID: 27427231

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP345989244	MIND4-17		345989-24-4	Price

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