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Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP)
Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients....
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122956/ https://www.ncbi.nlm.nih.gov/pubmed/33922601 http://dx.doi.org/10.3390/ijms22094417 |
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author | Lambert, Lester J Grotegut, Stefan Celeridad, Maria Gosalia, Palak Backer, Laurent JS De Bobkov, Andrey A Salaniwal, Sumeet Chung, Thomas DY Zeng, Fu-Yue Pass, Ian Lombroso, Paul J Cosford, Nicholas DP Tautz, Lutz |
author_facet | Lambert, Lester J Grotegut, Stefan Celeridad, Maria Gosalia, Palak Backer, Laurent JS De Bobkov, Andrey A Salaniwal, Sumeet Chung, Thomas DY Zeng, Fu-Yue Pass, Ian Lombroso, Paul J Cosford, Nicholas DP Tautz, Lutz |
author_sort | Lambert, Lester J |
collection | PubMed |
description | Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as “undruggable” and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer’s disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets. |
format | Online Article Text |
id | pubmed-8122956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81229562021-05-16 Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP) Lambert, Lester J Grotegut, Stefan Celeridad, Maria Gosalia, Palak Backer, Laurent JS De Bobkov, Andrey A Salaniwal, Sumeet Chung, Thomas DY Zeng, Fu-Yue Pass, Ian Lombroso, Paul J Cosford, Nicholas DP Tautz, Lutz Int J Mol Sci Article Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as “undruggable” and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer’s disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets. MDPI 2021-04-23 /pmc/articles/PMC8122956/ /pubmed/33922601 http://dx.doi.org/10.3390/ijms22094417 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lambert, Lester J Grotegut, Stefan Celeridad, Maria Gosalia, Palak Backer, Laurent JS De Bobkov, Andrey A Salaniwal, Sumeet Chung, Thomas DY Zeng, Fu-Yue Pass, Ian Lombroso, Paul J Cosford, Nicholas DP Tautz, Lutz Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP) |
title | Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP) |
title_full | Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP) |
title_fullStr | Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP) |
title_full_unstemmed | Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP) |
title_short | Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP) |
title_sort | development of a robust high-throughput screening platform for inhibitors of the striatal-enriched tyrosine phosphatase (step) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122956/ https://www.ncbi.nlm.nih.gov/pubmed/33922601 http://dx.doi.org/10.3390/ijms22094417 |
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