Structure-based Drug Design Using NMR

Jeeves, Mark; Quill, Lee; Overduin, Michael

doi:10.1002/9780470034590.emrstm1430

Cited by 1 publication

(1 citation statement)

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“…The discovery that Rho family GTPases are overexpressed, mutated and deregulated in several forms of cancers has motivated the search for inhibitors. Recent successes with the discovery of novel pockets and inhibitors of Ras [ 112 ] have further emboldened the field. Nonetheless, targeting the GTP binding site directly remains inherently challenging due to its picomolar nucleotide affinity and the high concentrations of GDP and GTP in cells.…”

Section: Targeting Rho Gtpase Signaling For Therapeutic Interventimentioning

confidence: 99%

Structural Mechanisms and Drug Discovery Prospects of Rho GTPases

Smithers

Overduin

2016

Cells

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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.

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Section: Targeting Rho Gtpase Signaling For Therapeutic Interventimentioning

confidence: 99%