Exploring the Therapeutic Potential of Protein Tyrosine Phosphatase 1B in hAPP-J20 Mouse Model of Alzheimer's Disease

Ghalayini, Judy

doi:10.1523/jneurosci.0852-20.2020

Cited by 4 publications

(2 citation statements)

References 20 publications

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“…Furthermore, PTP1B has been linked to other important diseases such as breast cancer, metabolic syndrome, immunological alterations, or hepatic disorders [13] . Indeed, this enzyme has been recently related with neurological disorders like Alzheimer's disease [14,15] . A large number of PTP1B inhibitor‐based anti‐diabetes molecules have been reported in the literature to date [16–18] .…”

Section: Introductionmentioning

confidence: 99%

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A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core

et al. 2021

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Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold‐hopping approach to vary the pyrrole ring of the pyrrolo[1,2‐a]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end‐point free‐energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo model, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained.

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Section: Introductionmentioning

confidence: 99%

“…[13] Indeed, this enzyme has been recently related with neurological disorders like Alzheimer's disease. [14,15] A large number of PTP1B inhibitorbased anti-diabetes molecules have been reported in the literature to date. [16][17][18] However, only non-competitive inhibitors have entered clinical trials viz.…”

Section: Introductionmentioning

confidence: 99%

A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core

et al. 2021

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Does Metabolic Manager Show Encouraging Outcomes in Alzheimer's?: Challenges and Opportunity for Protein Tyrosine Phosphatase 1b Inhibitors

Singh,

Jain,

Paliwal

et al. 2024

Drug Development Research

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Protein tyrosine phosphatase 1b (PTP1b) is a member of the protein tyrosine phosphatase (PTP) enzyme group and encoded as PTP1N gene. Studies have evidenced an overexpression of the PTP1b enzyme in metabolic syndrome, anxiety, schizophrenia, neurodegeneration, and neuroinflammation. PTP1b inhibitor negatively regulates insulin and leptin pathways and has been explored as an antidiabetic agent in various clinical trials. Notably, the preclinical studies have shown that recuperating metabolic dysfunction and dyshomeostasis can reverse cognition and could be a possible approach to mitigate multifaceted Alzheimer's disease (AD). PTP1b inhibitor thus has attracted attention in neuroscience, though the development is limited to the preclinical stage, and its exploration in large clinical trials is warranted. This review provides an insight on the development of PTP1b inhibitors from different sources in diabesity. The crosstalk between metabolic dysfunction and insulin insensitivity in AD and type‐2 diabetes has also been highlighted. Furthermore, this review presents the significance of PTP1b inhibition in AD based on pathophysiological facets, and recent evidences from preclinical and clinical studies.

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Role of Non-Receptor-Type Tyrosine Phosphatases in Brain-Related Diseases

Ding

Wang

2023

Mol Neurobiol

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Exploring the Therapeutic Potential of Protein Tyrosine Phosphatase 1B in hAPP-J20 Mouse Model of Alzheimer's Disease

Cited by 4 publications

References 20 publications

A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core

A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core

Does Metabolic Manager Show Encouraging Outcomes in Alzheimer's?: Challenges and Opportunity for Protein Tyrosine Phosphatase 1b Inhibitors

Role of Non-Receptor-Type Tyrosine Phosphatases in Brain-Related Diseases

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