PMID- 25093460
OWN - NLM
STAT- MEDLINE
DCOM- 20150409
LR  - 20220330
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 12
IP  - 8
DP  - 2014 Aug
TI  - Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse 
      model of Alzheimer's disease.
PG  - e1001923
LID - 10.1371/journal.pbio.1001923 [doi]
LID - e1001923
AB  - STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific 
      phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and 
      alpha-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.
FAU - Xu, Jian
AU  - Xu J
AD  - Child Study Center, Yale University, New Haven, Connecticut, United States of 
      America.
FAU - Chatterjee, Manavi
AU  - Chatterjee M
AD  - Child Study Center, Yale University, New Haven, Connecticut, United States of 
      America.
FAU - Baguley, Tyler D
AU  - Baguley TD
AD  - Department of Chemistry, Yale University, New Haven, Connecticut, United States 
      of America.
FAU - Brouillette, Jonathan
AU  - Brouillette J
AD  - Child Study Center, Yale University, New Haven, Connecticut, United States of 
      America.
FAU - Kurup, Pradeep
AU  - Kurup P
AD  - Child Study Center, Yale University, New Haven, Connecticut, United States of 
      America.
FAU - Ghosh, Debolina
AU  - Ghosh D
AD  - Child Study Center, Yale University, New Haven, Connecticut, United States of 
      America.
FAU - Kanyo, Jean
AU  - Kanyo J
AD  - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, 
      Connecticut, United States of America.
FAU - Zhang, Yang
AU  - Zhang Y
AD  - 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.
FAU - Seyb, Kathleen
AU  - Seyb K
AD  - Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, 
      Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America.
FAU - Ononenyi, Chimezie
AU  - Ononenyi C
AD  - Child Study Center, Yale University, New Haven, Connecticut, United States of 
      America.
FAU - Foscue, Ethan
AU  - Foscue E
AD  - Child Study Center, Yale University, New Haven, Connecticut, United States of 
      America.
FAU - Anderson, George M
AU  - Anderson GM
AD  - 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.
FAU - Gresack, Jodi
AU  - Gresack J
AD  - Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 
      New York, New York, United States of America.
FAU - Cuny, Gregory D
AU  - Cuny GD
AD  - Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, 
      Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America.
FAU - Glicksman, Marcie A
AU  - Glicksman MA
AD  - Laboratory for Drug Discovery in Neurodegeneration and Department of Neurology, 
      Brigham and Women's Hospital, Cambridge, Massachusetts, United States of America.
FAU - Greengard, Paul
AU  - Greengard P
AD  - Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 
      New York, New York, United States of America.
FAU - Lam, TuKiet T
AU  - Lam TT
AD  - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, 
      Connecticut, United States of America.
FAU - Tautz, Lutz
AU  - Tautz L
AD  - Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research 
      Institute, La Jolla, California, United States of America.
FAU - Nairn, Angus C
AU  - Nairn AC
AD  - Department of Psychiatry, Yale University, New Haven, Connecticut, United States 
      of America.
FAU - Ellman, Jonathan A
AU  - Ellman JA
AD  - Department of Chemistry, Yale University, New Haven, Connecticut, United States 
      of America.
FAU - Lombroso, Paul J
AU  - Lombroso PJ
AD  - 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.
LA  - eng
GR  - MH091037/MH/NIMH NIH HHS/United States
GR  - R01 GM054051/GM/NIGMS NIH HHS/United States
GR  - AG047781/AG/NIA NIH HHS/United States
GR  - DA024860/DA/NIDA NIH HHS/United States
GR  - R01 AG047781/AG/NIA NIH HHS/United States
GR  - GM054051/GM/NIGMS NIH HHS/United States
GR  - MH095532/MH/NIMH NIH HHS/United States
GR  - MH52711/MH/NIMH NIH HHS/United States
GR  - NS04933901/NS/NINDS NIH HHS/United States
GR  - R03 MH095532/MH/NIMH NIH HHS/United States
GR  - P30 DA018343/DA/NIDA NIH HHS/United States
GR  - PL1 DA024860/DA/NIDA NIH HHS/United States
GR  - R01 MH052711/MH/NIMH NIH HHS/United States
GR  - R01 MH091037/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140805
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine)
RN  - 0 (Benzothiepins)
RN  - 0 (Enzyme Inhibitors)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
RN  - EC 3.1.3.48 (Ptpn5 protein, mouse)
RN  - K848JZ4886 (Cysteine)
SB  - IM
CIN - A Novel Phosphatase Inhibitor May Be a STEP Toward Ameliorating Cognitive 
      Dysfunction.
MH  - Alzheimer Disease/complications/*drug therapy/*enzymology/pathology
MH  - Amino Acid Sequence
MH  - Animals
MH  - Benzothiepins/pharmacology/therapeutic use
MH  - Catalytic Domain
MH  - Cell Death/drug effects
MH  - Cerebral Cortex/pathology
MH  - Cognition Disorders/complications/*drug therapy/*enzymology/pathology
MH  - Cysteine/metabolism
MH  - Disease Models, Animal
MH  - Enzyme Inhibitors/chemistry/pharmacology/*therapeutic use
MH  - High-Throughput Screening Assays
MH  - Humans
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Molecular Sequence Data
MH  - Neurons/drug effects/pathology
MH  - Phosphorylation/drug effects
MH  - Phosphotyrosine/metabolism
MH  - Protein Tyrosine Phosphatases, Non-Receptor/*antagonists & 
      inhibitors/chemistry/metabolism
MH  - Substrate Specificity/drug effects
PMC - PMC4122355
COIS- The authors declare that they have no competing interests.
EDAT- 2014/08/06 06:00
MHDA- 2015/04/10 06:00
PMCR- 2014/08/05
CRDT- 2014/08/06 06:00
PHST- 2014/01/31 00:00 [received]
PHST- 2014/06/26 00:00 [accepted]
PHST- 2014/08/06 06:00 [entrez]
PHST- 2014/08/06 06:00 [pubmed]
PHST- 2015/04/10 06:00 [medline]
PHST- 2014/08/05 00:00 [pmc-release]
AID - PBIOLOGY-D-14-00425 [pii]
AID - 10.1371/journal.pbio.1001923 [doi]
PST - epublish
SO  - PLoS Biol. 2014 Aug 5;12(8):e1001923. doi: 10.1371/journal.pbio.1001923. 
      eCollection 2014 Aug.