2381/43706
L Quinti
L
Quinti
M Casale
M
Casale
S Moniot
S
Moniot
TF Pais
TF
Pais
MJ Van Kanegan
MJ
Van Kanegan
LS Kaltenbach
LS
Kaltenbach
J Pallos
J
Pallos
RG Lim
RG
Lim
SD Naidu
SD
Naidu
H Runne
H
Runne
L Meisel
L
Meisel
NA Rauf
NA
Rauf
D Leyfer
D
Leyfer
MM Maxwell
MM
Maxwell
E Saiah
E
Saiah
JE Landers
JE
Landers
R Luthi-Carter
R
Luthi-Carter
R Abagyan
R
Abagyan
AT Dinkova-Kostova
AT
Dinkova-Kostova
C Steegborn
C
Steegborn
JL Marsh
JL
Marsh
DC Lo
DC
Lo
LM Thompson
LM
Thompson
AG Kazantsev
AG
Kazantsev
SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models
University of Leicester
2019
Animals
Cell Line
Disease Models, Animal
Dose-Response Relationship, Drug
Drosophila
Huntington Disease
NF-E2-Related Factor 2
Neuroprotective Agents
Rats
Sirtuin 2
Structure-Activity Relationship
Thiazoles
2019-04-04 12:28:59
Journal contribution
https://figshare.le.ac.uk/articles/journal_contribution/SIRT2-_and_NRF2-Targeting_Thiazole-Containing_Compound_with_Therapeutic_Activity_in_Huntington_s_Disease_Models/10213388
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.