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BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions

The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robu...

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Autores principales: Bery, Nicolas, Cruz-Migoni, Abimael, Bataille, Carole JR, Quevedo, Camilo E, Tulmin, Hanna, Miller, Ami, Russell, Angela, Phillips, Simon EV, Carr, Stephen B, Rabbitts, Terence H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039175/
https://www.ncbi.nlm.nih.gov/pubmed/29989546
http://dx.doi.org/10.7554/eLife.37122
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author Bery, Nicolas
Cruz-Migoni, Abimael
Bataille, Carole JR
Quevedo, Camilo E
Tulmin, Hanna
Miller, Ami
Russell, Angela
Phillips, Simon EV
Carr, Stephen B
Rabbitts, Terence H
author_facet Bery, Nicolas
Cruz-Migoni, Abimael
Bataille, Carole JR
Quevedo, Camilo E
Tulmin, Hanna
Miller, Ami
Russell, Angela
Phillips, Simon EV
Carr, Stephen B
Rabbitts, Terence H
author_sort Bery, Nicolas
collection PubMed
description The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells. These include KRAS, HRAS and NRAS and a variety of different mutations that mirror those found in human cancers with the major RAS effectors such as CRAF, PI3K and RALGDS. We highlighted the utility of these RAS biosensors by showing a RAS-binding compound is a potent pan-RAS-effector interactions inhibitor in cells. The RAS biosensors represent a useful tool to investigate and characterize the potency of anti-RAS inhibitors in cells and more generally any RAS protein-protein interaction (PPI) in cells.
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spelling pubmed-60391752018-07-11 BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions Bery, Nicolas Cruz-Migoni, Abimael Bataille, Carole JR Quevedo, Camilo E Tulmin, Hanna Miller, Ami Russell, Angela Phillips, Simon EV Carr, Stephen B Rabbitts, Terence H eLife Cancer Biology The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells. These include KRAS, HRAS and NRAS and a variety of different mutations that mirror those found in human cancers with the major RAS effectors such as CRAF, PI3K and RALGDS. We highlighted the utility of these RAS biosensors by showing a RAS-binding compound is a potent pan-RAS-effector interactions inhibitor in cells. The RAS biosensors represent a useful tool to investigate and characterize the potency of anti-RAS inhibitors in cells and more generally any RAS protein-protein interaction (PPI) in cells. eLife Sciences Publications, Ltd 2018-07-10 /pmc/articles/PMC6039175/ /pubmed/29989546 http://dx.doi.org/10.7554/eLife.37122 Text en © 2018, Bery et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Bery, Nicolas
Cruz-Migoni, Abimael
Bataille, Carole JR
Quevedo, Camilo E
Tulmin, Hanna
Miller, Ami
Russell, Angela
Phillips, Simon EV
Carr, Stephen B
Rabbitts, Terence H
BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
title BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
title_full BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
title_fullStr BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
title_full_unstemmed BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
title_short BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions
title_sort bret-based ras biosensors that show a novel small molecule is an inhibitor of ras-effector protein-protein interactions
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039175/
https://www.ncbi.nlm.nih.gov/pubmed/29989546
http://dx.doi.org/10.7554/eLife.37122
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