ArticlePLoS biology2014
Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.
Article in PLoS biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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Who cites it
81 citing papers in PubMed.
- Phosphatase Signaling as a Therapeutic Strategy in Schizophrenia.International journal of molecular sciences · 2026Review
- Effects of the STriatal Enriched Tyrosine Phosphatase (STEP) Inhibitor TC-2153 on Hippocampal Long-Term Depression and Synaptic Transmission: Paradoxical Effect on Phosphatase Activity and Role of Adenosine.CNS neuroscience & therapeutics · 2026Article
- Article
- Vapor phase of white thyme essential oil: effect on Candida albicans and preservation of Lactobacillus species in the context of vulvovaginal candidiasis.BMC complementary medicine and therapies · 2025Article
- Anticancer Effect of Nature-Inspired Indolizine-Based Pentathiepines in 2D and 3D Cellular Model.Cancers · 2025Article
- Resilience mechanisms underlying Alzheimer's disease.Metabolic brain disease · 2025Review
- Pentathiepins are an understudied molecular prism of biological activities.Archiv der Pharmazie · 2024Review
- VEGFD signaling balances stability and activity-dependent structural plasticity of dendrites.Cellular and molecular life sciences : CMLS · 2024Article
- Impaired bone morphogenetic protein (BMP) signaling pathways disrupt decidualization in endometriosis.Communications biology · 2024Article
- High-Throughput Discovery and Characterization of Covalent Inhibitors for Protein Tyrosine Phosphatases.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases.Brain sciences · 2023Review
- Unveiling the Molecular Footprint: Proteome-Based Biomarkers for Alzheimer's Disease.Proteomes · 2023Review
- Uncovering the Significance of STEP61 in Alzheimer's Disease: Structure, Substrates, and Interactome.Cellular and molecular neurobiology · 2023Review
- Ferulic Acid Improves Synaptic Plasticity and Cognitive Impairments by Alleviating the PP2B/DARPP-32/PP1 Axis-Mediated STEP Increase and Aβ Burden in Alzheimer's Disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Article
- Novel approaches to increase synaptic resilience as potential treatments for Alzheimer's disease.Seminars in cell & developmental biology · 2023Review
- Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.Nature reviews. Drug discovery · 2023Review
- Tyrosine phosphatase STEPMolecular brain · 2023Article
- On Associations between Fear-Induced Aggression,International journal of molecular sciences · 2023Article
- Detection of Cellular Target Engagement for Small-Molecule Modulators of Striatal-Enriched Protein Tyrosine Phosphatase (STEP).Methods in molecular biology (Clifton, N.J.) · 2023Article
- Moringa Oleifera Alleviates Aβ Burden and Improves Synaptic Plasticity and Cognitive Impairments in APP/PS1 Mice.Nutrients · 2022Article
21 more citing papers are in PubMed but not listed here.
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21 authors.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.