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.
authors.affiliation: Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Quinti
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Casale
authors.affiliation: Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moniot
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Pais
authors.affiliation: Department of Neurobiology, Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Van Kanegan
authors.affiliation: Department of Neurobiology, Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Kaltenbach
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Pallos
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Lim
authors.affiliation: Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Sharadha Dayalan
authors.initials: SD
authors.lastname: Naidu
authors.affiliation: Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Heike
authors.initials: H
authors.lastname: Runne
authors.affiliation: Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Meisel
authors.affiliation: Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Nazifa Abdul
authors.initials: NA
authors.lastname: Rauf
authors.affiliation: Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Leyfer
authors.affiliation: Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michele M
authors.initials: MM
authors.lastname: Maxwell
authors.affiliation: BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.affiliation: Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093-0747, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: 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.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.affiliation: Department of Neurobiology, Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.affiliation: 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.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
authors.affiliation: Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: akazantsev47@gmail.com.
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D013844:Thiazoles; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2