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Activation of Rho Family GTPases by Small Molecules
[Image: see text] Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis, and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characteri...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical
Society
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006448/ https://www.ncbi.nlm.nih.gov/pubmed/29746086 http://dx.doi.org/10.1021/acschembio.8b00038 |
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author | Palsuledesai, Charuta C. Surviladze, Zurab Waller, Anna Miscioscia, T. Fabiola Guo, Yuna Wu, Yang Strouse, Jake Romero, Elsa Salas, Virginia M. Curpan, Ramona Young, Susan Carter, Mark Foutz, Terry Galochkina, Zhanna Ames, Harold Haynes, Mark K. Edwards, Bruce S. Nicolotti, Orazio Luo, Li Ursu, Oleg Bologa, Cristian G. Oprea, Tudor I. Wandinger-Ness, Angela Sklar, Larry A. |
author_facet | Palsuledesai, Charuta C. Surviladze, Zurab Waller, Anna Miscioscia, T. Fabiola Guo, Yuna Wu, Yang Strouse, Jake Romero, Elsa Salas, Virginia M. Curpan, Ramona Young, Susan Carter, Mark Foutz, Terry Galochkina, Zhanna Ames, Harold Haynes, Mark K. Edwards, Bruce S. Nicolotti, Orazio Luo, Li Ursu, Oleg Bologa, Cristian G. Oprea, Tudor I. Wandinger-Ness, Angela Sklar, Larry A. |
author_sort | Palsuledesai, Charuta C. |
collection | PubMed |
description | [Image: see text] Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis, and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characterization of small molecule agonists of one or more of six Rho, Rab, and Ras family GTPases that were first identified through flow cytometry-based, multiplexed high-throughput screening of 200000 compounds. The activators were categorized into three distinct chemical families that are represented by three lead compounds having the highest activity. Virtual screening predicted additional compounds with potential GTPase activating properties. Secondary dose–response assays performed on compounds identified through these screens confirmed agonist activity of 43 compounds. While the lead and second most active small molecules acted as pan activators of multiple GTPase subfamilies, others showed partial selectivity for Ras and Rab proteins. The compounds did not stimulate nucleotide exchange by guanine nucleotide exchange factors and did not protect against GAP-stimulated GTP hydrolysis. The activating properties were caused by a reversible stabilization of the GTP-bound state and prolonged effector protein interactions. Notably, these compounds were active both in vitro and in cell-based assays, and small molecule-mediated changes in Rho GTPase activities were directly coupled to measurable changes in cytoskeletal rearrangements that dictate cell morphology. |
format | Online Article Text |
id | pubmed-6006448 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American
Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-60064482018-06-20 Activation of Rho Family GTPases by Small Molecules Palsuledesai, Charuta C. Surviladze, Zurab Waller, Anna Miscioscia, T. Fabiola Guo, Yuna Wu, Yang Strouse, Jake Romero, Elsa Salas, Virginia M. Curpan, Ramona Young, Susan Carter, Mark Foutz, Terry Galochkina, Zhanna Ames, Harold Haynes, Mark K. Edwards, Bruce S. Nicolotti, Orazio Luo, Li Ursu, Oleg Bologa, Cristian G. Oprea, Tudor I. Wandinger-Ness, Angela Sklar, Larry A. ACS Chem Biol [Image: see text] Ras and Ras-related small GTPases are key regulators of diverse cellular functions that impact cell growth, survival, motility, morphogenesis, and differentiation. They are important targets for studies of disease mechanisms as well as drug discovery. Here, we report the characterization of small molecule agonists of one or more of six Rho, Rab, and Ras family GTPases that were first identified through flow cytometry-based, multiplexed high-throughput screening of 200000 compounds. The activators were categorized into three distinct chemical families that are represented by three lead compounds having the highest activity. Virtual screening predicted additional compounds with potential GTPase activating properties. Secondary dose–response assays performed on compounds identified through these screens confirmed agonist activity of 43 compounds. While the lead and second most active small molecules acted as pan activators of multiple GTPase subfamilies, others showed partial selectivity for Ras and Rab proteins. The compounds did not stimulate nucleotide exchange by guanine nucleotide exchange factors and did not protect against GAP-stimulated GTP hydrolysis. The activating properties were caused by a reversible stabilization of the GTP-bound state and prolonged effector protein interactions. Notably, these compounds were active both in vitro and in cell-based assays, and small molecule-mediated changes in Rho GTPase activities were directly coupled to measurable changes in cytoskeletal rearrangements that dictate cell morphology. American Chemical Society 2018-05-10 2018-06-15 /pmc/articles/PMC6006448/ /pubmed/29746086 http://dx.doi.org/10.1021/acschembio.8b00038 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Palsuledesai, Charuta C. Surviladze, Zurab Waller, Anna Miscioscia, T. Fabiola Guo, Yuna Wu, Yang Strouse, Jake Romero, Elsa Salas, Virginia M. Curpan, Ramona Young, Susan Carter, Mark Foutz, Terry Galochkina, Zhanna Ames, Harold Haynes, Mark K. Edwards, Bruce S. Nicolotti, Orazio Luo, Li Ursu, Oleg Bologa, Cristian G. Oprea, Tudor I. Wandinger-Ness, Angela Sklar, Larry A. Activation of Rho Family GTPases by Small Molecules |
title | Activation of Rho Family GTPases by Small Molecules |
title_full | Activation of Rho Family GTPases by Small Molecules |
title_fullStr | Activation of Rho Family GTPases by Small Molecules |
title_full_unstemmed | Activation of Rho Family GTPases by Small Molecules |
title_short | Activation of Rho Family GTPases by Small Molecules |
title_sort | activation of rho family gtpases by small molecules |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006448/ https://www.ncbi.nlm.nih.gov/pubmed/29746086 http://dx.doi.org/10.1021/acschembio.8b00038 |
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