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Structural Mechanisms and Drug Discovery Prospects of Rho GTPases

Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling en...

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Autores principales: Smithers, Cameron C., Overduin, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931675/
https://www.ncbi.nlm.nih.gov/pubmed/27304967
http://dx.doi.org/10.3390/cells5020026
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author Smithers, Cameron C.
Overduin, Michael
author_facet Smithers, Cameron C.
Overduin, Michael
author_sort Smithers, Cameron C.
collection PubMed
description Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies.
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spelling pubmed-49316752016-07-08 Structural Mechanisms and Drug Discovery Prospects of Rho GTPases Smithers, Cameron C. Overduin, Michael Cells Review Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies. MDPI 2016-06-13 /pmc/articles/PMC4931675/ /pubmed/27304967 http://dx.doi.org/10.3390/cells5020026 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Smithers, Cameron C.
Overduin, Michael
Structural Mechanisms and Drug Discovery Prospects of Rho GTPases
title Structural Mechanisms and Drug Discovery Prospects of Rho GTPases
title_full Structural Mechanisms and Drug Discovery Prospects of Rho GTPases
title_fullStr Structural Mechanisms and Drug Discovery Prospects of Rho GTPases
title_full_unstemmed Structural Mechanisms and Drug Discovery Prospects of Rho GTPases
title_short Structural Mechanisms and Drug Discovery Prospects of Rho GTPases
title_sort structural mechanisms and drug discovery prospects of rho gtpases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931675/
https://www.ncbi.nlm.nih.gov/pubmed/27304967
http://dx.doi.org/10.3390/cells5020026
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