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

Luisa Quinti; Malcolm Casale; Sébastien Moniot; Teresa F. Pais; Michael J. Van Kanegan; Linda S. Kaltenbach; Judit Pallos; Ryan G. Lim; Sharadha Dayalan Naidu; Heike Runne; Lisa Meisel; Nazifa Abdul Rauf; Dmitriy Leyfer; Michele M. Maxwell; Eddine Saiah; John E. Landers; Ruth Luthi-Carter; Ruben Abagyan; Albena T. Dinkova-Kostova; Clemens Steegborn; J. Lawrence Marsh; Donald C. Lo; Leslie M. Thompson; Aleksey G. Kazantsev

doi:10.1016/j.chembiol.2016.05.015

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

Luisa Quinti, Malcolm Casale, Sébastien Moniot, Teresa F. Pais, Michael J. Van Kanegan, Linda S. Kaltenbach, Judit Pallos, Ryan G. Lim, Sharadha Dayalan Naidu, Heike Runne, Lisa Meisel, Nazifa Abdul Rauf, Dmitriy Leyfer, Michele M. Maxwell, Eddine Saiah, John E. Landers, Ruth Luthi-Carter, Ruben Abagyan, Albena T. Dinkova-Kostova, Clemens SteegbornJ. Lawrence Marsh, Donald C. Lo, Leslie M. Thompson, Aleksey G. Kazantsev

School of Medicine

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 (US)
Pages (from-to)	849-861
Number of pages	13
Journal	Cell Chemical Biology
Volume	23
Issue number	7
DOIs	https://doi.org/10.1016/j.chembiol.2016.05.015
State	Published - Jul 21 2016

ASJC Scopus subject areas

Biochemistry
Clinical Biochemistry
Molecular Biology
Molecular Medicine
Drug Discovery
Pharmacology

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Quinti, L., Casale, M., Moniot, S., Pais, T. F., Van Kanegan, M. J., Kaltenbach, L. S., Pallos, J., Lim, R. G., Naidu, S. D., Runne, H., Meisel, L., Rauf, N. A., Leyfer, D., Maxwell, M. M., Saiah, E., Landers, J. E., Luthi-Carter, R., Abagyan, R., Dinkova-Kostova, A. T., ... 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, 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 2016, 'SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models', Cell Chemical Biology, vol. 23, no. 7, pp. 849-861. https://doi.org/10.1016/j.chembiol.2016.05.015

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

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.",

author = "Luisa Quinti and Malcolm Casale and S{\'e}bastien Moniot and Pais, {Teresa F.} and {Van Kanegan}, {Michael J.} and Kaltenbach, {Linda S.} and Judit Pallos and Lim, {Ryan G.} and Naidu, {Sharadha Dayalan} and Heike Runne and Lisa Meisel and Rauf, {Nazifa Abdul} and Dmitriy Leyfer and Maxwell, {Michele M.} and Eddine Saiah and Landers, {John E.} and Ruth Luthi-Carter and Ruben Abagyan and Dinkova-Kostova, {Albena T.} and Clemens Steegborn and Marsh, {J. Lawrence} and Lo, {Donald C.} and Thompson, {Leslie M.} and Kazantsev, {Aleksey G.}",

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AU - Quinti, Luisa

AU - Casale, Malcolm

AU - Moniot, Sébastien

AU - Pais, Teresa F.

AU - Van Kanegan, Michael J.

AU - Kaltenbach, Linda S.

AU - Pallos, Judit

AU - Lim, Ryan G.

AU - Naidu, Sharadha Dayalan

AU - Runne, Heike

AU - Meisel, Lisa

AU - Rauf, Nazifa Abdul

AU - Leyfer, Dmitriy

AU - Maxwell, Michele M.

AU - Saiah, Eddine

AU - Landers, John E.

AU - Luthi-Carter, Ruth

AU - Abagyan, Ruben

AU - Dinkova-Kostova, Albena T.

AU - Steegborn, Clemens

AU - Marsh, J. Lawrence

AU - Lo, Donald C.

AU - Thompson, Leslie M.

AU - Kazantsev, Aleksey G.

PY - 2016/7/21

Y1 - 2016/7/21

N2 - 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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SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

Abstract

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