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SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.
Quinti, Luisa; Casale, Malcolm; Moniot, Sébastien; Pais, Teresa F; Van Kanegan, Michael J; Kaltenbach, Linda S; Pallos, Judit; Lim, Ryan G; Naidu, Sharadha Dayalan; Runne, Heike; Meisel, Lisa; Rauf, Nazifa Abdul; Leyfer, Dmitriy; Maxwell, Michele M; Saiah, Eddine; Landers, John E; Luthi-Carter, Ruth; Abagyan, Ruben; Dinkova-Kostova, Albena T; Steegborn, Clemens; Marsh, J Lawrence; Lo, Donald C; Thompson, Leslie M; Kazantsev, Aleksey G.
Afiliación
  • Quinti L; Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
  • Casale M; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
  • Moniot S; Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
  • Pais TF; Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal.
  • Van Kanegan MJ; Department of Neurobiology, Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710, USA.
  • Kaltenbach LS; Department of Neurobiology, Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710, USA.
  • Pallos J; Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
  • Lim RG; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
  • Naidu SD; Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
  • Runne H; Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
  • Meisel L; Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
  • Rauf NA; Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
  • Leyfer D; Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
  • Maxwell MM; Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
  • Saiah E; BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
  • Landers JE; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
  • Luthi-Carter R; Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
  • Abagyan R; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093-0747, USA.
  • Dinkova-Kostova AT; 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.
  • Steegborn C; Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
  • Marsh JL; Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
  • Lo DC; Department of Neurobiology, Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710, USA.
  • Thompson LM; 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.
  • Kazantsev AG; Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: akazantsev47@gmail.com.
Cell Chem Biol ; 23(7): 849-861, 2016 07 21.
Article en En | MEDLINE | ID: mdl-27427231
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Enfermedad de Huntington / Fármacos Neuroprotectores / Modelos Animales de Enfermedad / Factor 2 Relacionado con NF-E2 / Sirtuina 2 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Chem Biol Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles / Enfermedad de Huntington / Fármacos Neuroprotectores / Modelos Animales de Enfermedad / Factor 2 Relacionado con NF-E2 / Sirtuina 2 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Chem Biol Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos