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Targeting the Small GTPase Superfamily through Their Regulatory Proteins
The Ras superfamily of small GTPases are guanine‐nucleotide‐dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204875/ https://www.ncbi.nlm.nih.gov/pubmed/30869179 http://dx.doi.org/10.1002/anie.201900585 |
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author | Gray, Janine L. von Delft, Frank Brennan, Paul E. |
author_facet | Gray, Janine L. von Delft, Frank Brennan, Paul E. |
author_sort | Gray, Janine L. |
collection | PubMed |
description | The Ras superfamily of small GTPases are guanine‐nucleotide‐dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as “undruggable”. The GTP‐dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re‐evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell‐based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins. |
format | Online Article Text |
id | pubmed-7204875 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-72048752020-05-11 Targeting the Small GTPase Superfamily through Their Regulatory Proteins Gray, Janine L. von Delft, Frank Brennan, Paul E. Angew Chem Int Ed Engl Reviews The Ras superfamily of small GTPases are guanine‐nucleotide‐dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as “undruggable”. The GTP‐dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re‐evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell‐based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins. John Wiley and Sons Inc. 2020-01-30 2020-04-16 /pmc/articles/PMC7204875/ /pubmed/30869179 http://dx.doi.org/10.1002/anie.201900585 Text en © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Reviews Gray, Janine L. von Delft, Frank Brennan, Paul E. Targeting the Small GTPase Superfamily through Their Regulatory Proteins |
title | Targeting the Small GTPase Superfamily through Their Regulatory Proteins |
title_full | Targeting the Small GTPase Superfamily through Their Regulatory Proteins |
title_fullStr | Targeting the Small GTPase Superfamily through Their Regulatory Proteins |
title_full_unstemmed | Targeting the Small GTPase Superfamily through Their Regulatory Proteins |
title_short | Targeting the Small GTPase Superfamily through Their Regulatory Proteins |
title_sort | targeting the small gtpase superfamily through their regulatory proteins |
topic | Reviews |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204875/ https://www.ncbi.nlm.nih.gov/pubmed/30869179 http://dx.doi.org/10.1002/anie.201900585 |
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