Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy

Curr Top Med Chem. 2005;5(2):215-29. doi: 10.2174/1568026053507723.


This paper reviews recent progress in the design and evaluation of MEK inhibitors as cancer therapeutics. Activation of the Ras / Raf / MEK / MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic and 30% of lung cancers. Recently, B-Raf mutations have been identified in more than 60% of malignant melanomas and from 40-70% of papillary thyroid cancers. MEK, a dual specificity kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. Representative examples of both ATP competitive and non-competitive inhibitors as well as natural product based inhibitors will be discussed.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Biological Factors
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Neoplasms / drug therapy*
  • Neoplasms / physiopathology
  • Signal Transduction / drug effects


  • Antineoplastic Agents
  • Biological Factors
  • Enzyme Inhibitors
  • MAP Kinase Kinase Kinases