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.
Luisa Quinti  1 ,  Malcolm Casale  2 ,  Sébastien Moniot  3 ,  Teresa F Pais  4 ,  Michael J Van Kanegan  5 ,  Linda S Kaltenbach  5 ,  Judit Pallos  6 ,  Ryan G Lim  7 ,  Sharadha Dayalan Naidu  8 ,  Heike Runne  9 ,  Lisa Meisel  3 ,  Nazifa Abdul Rauf  1 ,  Dmitriy Leyfer  1 ,  Michele M Maxwell  1 ,  Eddine Saiah  10 ,  John E Landers  11 ,  Ruth Luthi-Carter  9 ,  Ruben Abagyan  12 ,  Albena T Dinkova-Kostova  13 ,  Clemens Steegborn  3 ,  J Lawrence Marsh  6 ,  Donald C Lo  5 ,  Leslie M Thompson  14 ,  Aleksey G Kazantsev  15
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: [email protected].
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.

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