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Cells 2016, 5(2), 26;

Structural Mechanisms and Drug Discovery Prospects of Rho GTPases

Department of Biochemistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
Author to whom correspondence should be addressed.
Academic Editor: Bor Luen Tang
Received: 12 April 2016 / Revised: 28 May 2016 / Accepted: 7 June 2016 / Published: 13 June 2016
(This article belongs to the Special Issue Regulation and Function of Small GTPases)
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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. View Full-Text
Keywords: cancer therapy; signal transduction; GTPase; Rho; RhoA; Rac1; Cdc42; GEF cancer therapy; signal transduction; GTPase; Rho; RhoA; Rac1; Cdc42; GEF

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Smithers, C.C.; Overduin, M. Structural Mechanisms and Drug Discovery Prospects of Rho GTPases. Cells 2016, 5, 26.

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