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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
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.
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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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