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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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.
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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