2. Academic Validation
  3. SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

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

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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