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Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B
Protein phosphorylation is a prevalent and ubiquitous mechanism of regulation. Kinases are popular drug targets, but identifying selective phosphatase inhibitors has been challenging. Here, we used surface plasmon resonance to design a method to enable target-based discovery of selective serine/thre...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108835/ https://www.ncbi.nlm.nih.gov/pubmed/30057111 http://dx.doi.org/10.1016/j.cell.2018.06.030 |
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author | Krzyzosiak, Agnieszka Sigurdardottir, Anna Luh, Laura Carrara, Marta Das, Indrajit Schneider, Kim Bertolotti, Anne |
author_facet | Krzyzosiak, Agnieszka Sigurdardottir, Anna Luh, Laura Carrara, Marta Das, Indrajit Schneider, Kim Bertolotti, Anne |
author_sort | Krzyzosiak, Agnieszka |
collection | PubMed |
description | Protein phosphorylation is a prevalent and ubiquitous mechanism of regulation. Kinases are popular drug targets, but identifying selective phosphatase inhibitors has been challenging. Here, we used surface plasmon resonance to design a method to enable target-based discovery of selective serine/threonine phosphatase inhibitors. The method targeted a regulatory subunit of protein phosphatase 1, PPP1R15B (R15B), a negative regulator of proteostasis. This yielded Raphin1, a selective inhibitor of R15B. In cells, Raphin1 caused a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis. In vitro, Raphin1 inhibits the recombinant R15B-PP1c holoenzyme, but not the closely related R15A-PP1c, by interfering with substrate recruitment. Raphin1 was orally bioavailable, crossed the blood-brain barrier, and demonstrated efficacy in a mouse model of Huntington’s disease. This identifies R15B as a druggable target and provides a platform for target-based discovery of inhibitors of serine/threonine phosphatases. |
format | Online Article Text |
id | pubmed-6108835 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-61088352018-08-27 Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B Krzyzosiak, Agnieszka Sigurdardottir, Anna Luh, Laura Carrara, Marta Das, Indrajit Schneider, Kim Bertolotti, Anne Cell Article Protein phosphorylation is a prevalent and ubiquitous mechanism of regulation. Kinases are popular drug targets, but identifying selective phosphatase inhibitors has been challenging. Here, we used surface plasmon resonance to design a method to enable target-based discovery of selective serine/threonine phosphatase inhibitors. The method targeted a regulatory subunit of protein phosphatase 1, PPP1R15B (R15B), a negative regulator of proteostasis. This yielded Raphin1, a selective inhibitor of R15B. In cells, Raphin1 caused a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis. In vitro, Raphin1 inhibits the recombinant R15B-PP1c holoenzyme, but not the closely related R15A-PP1c, by interfering with substrate recruitment. Raphin1 was orally bioavailable, crossed the blood-brain barrier, and demonstrated efficacy in a mouse model of Huntington’s disease. This identifies R15B as a druggable target and provides a platform for target-based discovery of inhibitors of serine/threonine phosphatases. Cell Press 2018-08-23 /pmc/articles/PMC6108835/ /pubmed/30057111 http://dx.doi.org/10.1016/j.cell.2018.06.030 Text en © 2018 MRC Laboratory of Molecular Biology http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Krzyzosiak, Agnieszka Sigurdardottir, Anna Luh, Laura Carrara, Marta Das, Indrajit Schneider, Kim Bertolotti, Anne Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B |
title | Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B |
title_full | Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B |
title_fullStr | Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B |
title_full_unstemmed | Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B |
title_short | Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B |
title_sort | target-based discovery of an inhibitor of the regulatory phosphatase ppp1r15b |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108835/ https://www.ncbi.nlm.nih.gov/pubmed/30057111 http://dx.doi.org/10.1016/j.cell.2018.06.030 |
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