title: Approaches to Ras signaling modulation and treatment of Ras-dependent disorders: a patent review (2007--present).
abstract: BACKGROUND
  Ras proteins are small GTPases molecular switches that cycle through two alternative conformational states, a GDP-bound inactive state and a GTP-bound active state. In the active state, Ras proteins interact with and modulate the activity of several downstream effectors regulating key cellular processes including proliferation, differentiation, survival, senescence, migration and metabolism. Activating mutations of RAS genes and of genes encoding Ras signaling members have a great incidence in proliferative disorders, such as cancer, immune and inflammatory diseases and developmental syndromes. Therefore, Ras and Ras signaling represent important clinical targets for the design and development of pharmaceutically active agents, including anticancer agents.
  
  
  METHODS
  The authors summarize methods available to down-regulate the Ras pathway and review recent patents covering Ras signaling modulators, as well as methods designed to kill specifically cancer cells bearing activated RAS oncogene.
  
  
  CONCLUSIONS
  Targeted therapy approach based on direct targeting of molecules specifically altered in Ras-dependent diseases is pursued with molecules that down-regulate expression or inhibit the biological function of mutant Ras or Ras signaling members. The low success rate in a clinical setting of molecules targeting activated members of the Ras pathway may require development of novel approaches, including combined and synthetic lethal therapies.
authors.affiliation: University of Milano-Bicocca, Department of Biotechnology and Biosciences, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sacco
authors.forename: Michela
authors.initials: M
authors.lastname: Spinelli
authors.forename: Marco
authors.initials: M
authors.lastname: Vanoni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011905:Genes, ras; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010330:Patents as Topic; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018631:ras Proteins