title: 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-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.
authors.affiliation: 1] Max Planck Institute of Molecular Physiology, Dortmund, Germany. [2] Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Spiegel
authors.affiliation: 1] Max Planck Institute of Molecular Physiology, Dortmund, Germany. [2] Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Cromm
authors.affiliation: 1] Max Planck Institute of Molecular Physiology, Dortmund, Germany. [2] Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Zimmermann
authors.affiliation: 1] Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany. [2] Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.
authors.forename: Tom N
authors.initials: TN
authors.lastname: Grossmann
authors.affiliation: 1] Max Planck Institute of Molecular Physiology, Dortmund, Germany. [2] Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000595:Amino Acid Sequence; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009154:Mutation; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D054852:Small Molecule Libraries; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D011494:Protein Kinases; C111878:cAMP phosphodiesterase kinase; D018631:ras Proteins