title: Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.
abstract: STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Manavi
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Baguley
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brouillette
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kurup
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Debolina
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Jean
authors.initials: J
authors.lastname: Kanyo
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America; Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Seyb
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Chimezie
authors.initials: C
authors.lastname: Ononenyi
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Ethan
authors.initials: E
authors.lastname: Foscue
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America; Department of Laboratory Medicine, Yale University, New Haven, Connecticut, United States of America.
authors.forename: George M
authors.initials: GM
authors.lastname: Anderson
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, United States of America.
authors.forename: Jodi
authors.initials: J
authors.lastname: Gresack
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America.
authors.forename: Marcie A
authors.initials: MA
authors.lastname: Glicksman
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: TuKiet T
authors.initials: TT
authors.lastname: Lam
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Lutz
authors.initials: L
authors.lastname: Tautz
authors.affiliation: Department of Psychiatry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut, United States of America; Department of Psychiatry, Yale University, New Haven, Connecticut, United States of America; Department of Neurobiology, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology / Q000627:therapeutic use; D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: C559038:8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine; D001582:Benzothiepins; D004791:Enzyme Inhibitors; D019000:Phosphotyrosine; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse; D003545:Cysteine
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