J Spiegel, PM Cromm, G Zimmermann, TN Grossmann, H Waldmann
Nat Chem Biol
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-Ras(G12C) 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.