title: Novel mitogen-activated protein kinase kinase inhibitors.
abstract: BACKGROUND
  the development of new drugs over the last few decades has targeted specific proteins thought to be a key to the disease state. MAPK kinases 1 and 2 (commonly known as MEK1-2) represent such proteins as they lie downstream of important drug targets for oncology, such as EGFR, RAS and RAF. Several MEK1-2 inhibitors are currently in Phase I and II clinical trials in oncology.
  
  
  METHODS
  this review of current literature and recent conferences provides a background on the RAS-RAF-MEK-ERK signaling pathway and a discussion of early MEK inhibitors. The potential of MEK1-2 inhibitors for the treatment of inflammation is briefly presented. Preclinical and early clinical results are discussed for MEK inhibitors currently in development. Completed clinical trials of MEK inhibitors in oncology include some disappointments as well as some promising signs of the value of these compounds and we discuss the potential for MEK inhibitors as monotherapy and their use in drug combinations.
  
  
  CONCLUSIONS
  the utility of MEK inhibitors as anticancer agents will depend on careful patient selection based on the presence of mutations in genes such as KRAS and BRAF, the identification of additional predictive biomarkers, and an improved understanding of the benefit of drug combinations utilizing both established and emerging therapeutics.
authors.affiliation: Biogen Idec, San Diego, California, USA markschapman@san.rr.com.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Chapman
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Miner
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D011905:Genes, ras; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins