title: New small-molecule inhibitors of mitogen-activated protein kinase kinase.
abstract: BACKGROUND
  Overexpression of the Ras/Raf/MEK/ERK (extracellular-signal-regulated kinase) pathway is associated with the formation, progression and survival of tumours and has also been implicated in a diverse range of therapeutic areas such as arthritis, organ transplant rejection, asthma and developmental disorders. One approach to down regulation of this pathway is through the inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2).
  
  
  OBJECTIVE
  The importance of the mitogen-activated protein kinase (MAPK) pathway, MEK1/2 as a therapeutic target and early MEK1/2 inhibitors is discussed, followed by an overview of recent patent activity in the area.
  
  
  METHODS
  The patent literature was searched for inhibitors of MEK1/2 published within the last three years; these results are described. Other relevant publications that provide further insight into the discovery and development of these compounds are also discussed.
  
  
  CONCLUSIONS
  The determination of a crystal structure with inhibitor bound has allowed the design of exquisitely selective and potent inhibitors of MEK1/2. Several allosteric inhibitors have advanced to clinical trial and shown some efficacy in cancer as single agents, but the future application of MEK1/2 inhibitors is likely to be either in combination with other therapies or in disorders which are genetically defined as being dependent on the MAPK pathway.
authors.affiliation: University of Auckland, Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, Private Bag 92019, Auckland 1142, New Zealand +64 9 3737599, ext. 86149 ; +64 9 3737502 ; j.spicer@auckland.ac.nz.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer