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

Published

Journal Article

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.

Full Text

Cited Authors

  • Quinti, L; Casale, M; Moniot, S; Pais, TF; Van Kanegan, MJ; Kaltenbach, LS; Pallos, J; Lim, RG; Naidu, SD; Runne, H; Meisel, L; Rauf, NA; Leyfer, D; Maxwell, MM; Saiah, E; Landers, JE; Luthi-Carter, R; Abagyan, R; Dinkova-Kostova, AT; Steegborn, C; Marsh, JL; Lo, DC; Thompson, LM; Kazantsev, AG

Published Date

  • July 14, 2016

Published In

Volume / Issue

  • 23 / 7

Start / End Page

  • 849 - 861

PubMed ID

  • 27427231

Pubmed Central ID

  • 27427231

Electronic International Standard Serial Number (EISSN)

  • 2451-9448

International Standard Serial Number (ISSN)

  • 2451-9456

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2016.05.015

Language

  • eng