Novel mitogen-activated protein kinase kinase inhibitors

Expert Opin Investig Drugs. 2011 Feb;20(2):209-20. doi: 10.1517/13543784.2011.548803.

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Clinical Trials as Topic
  • Genes, ras
  • Humans
  • Inflammation / drug therapy*
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Molecular Targeted Therapy*
  • Mutation
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction
  • raf Kinases / antagonists & inhibitors
  • raf Kinases / genetics
  • raf Kinases / metabolism
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • raf Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins