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

Publication ,  Journal Article
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 ...
Published in: Cell chemical biology
July 2016

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.

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Published In

Cell chemical biology

DOI

EISSN

2451-9448

ISSN

2451-9456

Publication Date

July 2016

Volume

23

Issue

7

Start / End Page

849 / 861

Related Subject Headings

  • Thiazoles
  • Structure-Activity Relationship
  • Sirtuin 2
  • Rats
  • Neuroprotective Agents
  • NF-E2-Related Factor 2
  • Huntington Disease
  • Drosophila
  • Dose-Response Relationship, Drug
  • Disease Models, Animal
 

Citation

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Quinti, L., Casale, M., Moniot, S., Pais, T. F., Van Kanegan, M. J., Kaltenbach, L. S., … Kazantsev, A. G. (2016). SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models. Cell Chemical Biology, 23(7), 849–861. https://doi.org/10.1016/j.chembiol.2016.05.015
Quinti, Luisa, Malcolm Casale, Sébastien Moniot, Teresa F. Pais, Michael J. Van Kanegan, Linda S. Kaltenbach, Judit Pallos, et al. “SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.Cell Chemical Biology 23, no. 7 (July 2016): 849–61. https://doi.org/10.1016/j.chembiol.2016.05.015.
Quinti L, Casale M, Moniot S, Pais TF, Van Kanegan MJ, Kaltenbach LS, et al. SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models. Cell chemical biology. 2016 Jul;23(7):849–61.
Quinti, Luisa, et al. “SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.Cell Chemical Biology, vol. 23, no. 7, July 2016, pp. 849–61. Epmc, doi:10.1016/j.chembiol.2016.05.015.
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. SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models. Cell chemical biology. 2016 Jul;23(7):849–861.

Published In

Cell chemical biology

DOI

EISSN

2451-9448

ISSN

2451-9456

Publication Date

July 2016

Volume

23

Issue

7

Start / End Page

849 / 861

Related Subject Headings

  • Thiazoles
  • Structure-Activity Relationship
  • Sirtuin 2
  • Rats
  • Neuroprotective Agents
  • NF-E2-Related Factor 2
  • Huntington Disease
  • Drosophila
  • Dose-Response Relationship, Drug
  • Disease Models, Animal