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Small-molecule modulation of Ras signaling

Abstract

Despite intense efforts in pharmaceutical industry and academia, a therapeutic grip on oncogenic Ras proteins has remained elusive. Mutated Ras is associated with 20−30% of all human cancers often not responsive to established therapies. In particular, K-Ras, the most frequently mutated Ras isoform, is considered one of the most important but 'undruggable' targets in cancer research. Recently, new cavities on Ras for small-molecule ligands were identified, and selective direct targeting of mutated K-RasG12C has become possible for what is to our knowledge the first time. In addition, impairment of Ras spatial organization, in particular via targeting the prenyl-binding Ras chaperone PDEδ, has opened a fresh perspective in anticancer research. These recent advances fuel hopes for the development of new drugs targeting Ras.

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Figure 1: Regulation of Ras activity.
Figure 2: Strategies for targeting Ras.
Figure 3: Structural basis for orthosteric inhibition of Ras-GEF interactions.
Figure 4: Covalent inhibitors targeting Cys12 of mutated K-RasG12C.
Figure 5: Structural basis for orthosteric inhibition of Ras−effector interactions.
Figure 6: Post-translational processing of Ras.
Figure 7: Structural basis for inhibition of the K-Ras−PDEδ interaction.
Figure 8: Inhibition of Rab-effector interactions.

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Acknowledgements

J.S. acknowledges financial support by Fonds der Chemischen Industrie. P.M.C. is thankful to the Studienstiftung des deutschen Volkes for a fellowship. T.N.G. thanks the German Research Foundation (DFG, Emmy Noether program GR3592/2-1) for financial support.

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Correspondence to Tom N Grossmann or Herbert Waldmann.

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G.Z. and H.W. are inventors on a Max-Planck-Gesellschaft patent application concerning Ras-PDEδ inhibitors.

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Spiegel, J., Cromm, P., Zimmermann, G. et al. Small-molecule modulation of Ras signaling. Nat Chem Biol 10, 613–622 (2014). https://doi.org/10.1038/nchembio.1560

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