Projects per year
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.
Original language | English |
---|---|
Pages (from-to) | 849-861 |
Number of pages | 13 |
Journal | Cell Chemical Biology |
Volume | 23 |
Issue number | 7 |
Early online date | 14 Jul 2016 |
DOIs | |
Publication status | Published - 21 Jul 2016 |
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Molecular Biology
- Molecular Medicine
- Drug Discovery
- Pharmacology
Fingerprint
Dive into the research topics of 'SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models'. Together they form a unique fingerprint.Projects
- 2 Finished
-
The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)
Dinkova-Kostova, A. (Investigator)
Biotechnology and Biological Sciences Research Council
30/09/14 → 27/02/18
Project: Research
-
Activation of the Heat Shock Response by Sulfhydryl-Reactive Chemoprotective Agents
Dinkova-Kostova, A. (Investigator)
Biotechnology and Biological Sciences Research Council
1/04/12 → 30/09/15
Project: Research
Profiles
-
Dinkova-Kostova, Albena
- Cancer Research - Professor (Teaching and Research) of Chemical Biology
Person: Academic