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

Title data

Quinti, Luisa ; Casale, Malcolm ; Moniot, Sébastien ; Pais, Teresa Faria ; van Kanegan, Michael J. ; Kaltenbach, Linda S. ; Pallos, Judit ; Lim, Ryan G. ; Naidu, Sharadha Dayalan ; Runne, Heike ; Meisel, Lisa ; Rauf, Nazifa Abdul ; Leyfer, Dmitriy ; Maxwell, Michelle M. ; Saiah, Eddine ; Landers, John E. ; Luthi-Carter, Ruth ; Abagyan, Ruben ; Dinkova-Kostova, Albena T. ; Steegborn, Clemens ; Marsh, J. Lawrence ; Lo, Donald C. ; Thompson, Leslie M. ; Kazantsev, Aleksey G.:
SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.
In: Cell Chemical Biology. Vol. 23 (21 July 2016) Issue 7 . - pp. 849-861.
ISSN 2451-9456
DOI: https://doi.org/10.1016/j.chembiol.2016.05.015

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science
500 Science > 540 Chemistry
Date Deposited: 06 Apr 2017 08:51
Last Modified: 01 Oct 2018 10:52
URI: https://eref.uni-bayreuth.de/id/eprint/36766