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

Cell Chem Biol. 2016 Jul 21;23(7):849-861. doi: 10.1016/j.chembiol.2016.05.015. Epub 2016 Jul 14.

Authors

Luisa Quinti¹, Malcolm Casale², Sébastien Moniot³, Teresa F Pais⁴, Michael J Van Kanegan⁵, Linda S Kaltenbach⁵, Judit Pallos⁶, Ryan G Lim⁷, Sharadha Dayalan Naidu⁸, Heike Runne⁹, Lisa Meisel³, Nazifa Abdul Rauf¹, Dmitriy Leyfer¹, Michele M Maxwell¹, Eddine Saiah¹⁰, John E Landers¹¹, Ruth Luthi-Carter⁹, Ruben Abagyan¹², Albena T Dinkova-Kostova¹³, Clemens Steegborn³, J Lawrence Marsh⁶, Donald C Lo⁵, Leslie M Thompson¹⁴, Aleksey G Kazantsev¹⁵

Affiliations

¹ Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
² Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
³ Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
⁴ Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal.
⁵ Department of Neurobiology, Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710, USA.
⁶ Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
⁷ Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
⁸ Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
⁹ Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
¹⁰ BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
¹¹ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
¹² Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093-0747, USA.
¹³ Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK; Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁴ Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.
¹⁵ Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: akazantsev47@gmail.com.

PMID: 27427231
DOI: 10.1016/j.chembiol.2016.05.015

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Disease Models, Animal*
Dose-Response Relationship, Drug
Drosophila
Huntington Disease / drug therapy*
Huntington Disease / metabolism
NF-E2-Related Factor 2 / antagonists & inhibitors*
NF-E2-Related Factor 2 / metabolism
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Neuroprotective Agents / therapeutic use
Rats
Sirtuin 2 / antagonists & inhibitors*
Sirtuin 2 / deficiency
Sirtuin 2 / metabolism
Structure-Activity Relationship
Thiazoles / chemistry
Thiazoles / pharmacology*
Thiazoles / therapeutic use*

Substances

NF-E2-Related Factor 2
Neuroprotective Agents
Nfe2l2 protein, mouse
Thiazoles
Sirt2 protein, mouse
Sirtuin 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding