Allosteric modulators of MEK1: drug design and discovery

Chem Biol Drug Des. 2016 Oct;88(4):485-97. doi: 10.1111/cbdd.12780. Epub 2016 Jun 1.

Abstract

Mitogen-activated protein kinase kinase (MAPKK, MEK) mediates signal transduction, controlling cell proliferation and survival. MEK occupies a key downstream position in the Ras-Raf-MEK-ERK signaling pathway, implying that inhibition of MEK will potently suppress tumor cell growth, with potential applications in cancer therapy. Based on the promising therapeutic effects of MEK modulators, continued efforts have been made in this class. Here, we review the discovery and development of MEK1 allosteric modulators, classifying them into four structural groups. The allosteric mechanisms and recent clinical progress involving these modulators are also reviewed.

Keywords: MEK1; allosteric mechanism; allosteric modulators; cancer treatment; signaling pathway.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation
  • Drug Design*
  • Drug Discovery
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 1 / chemistry
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects

Substances

  • Flavonoids
  • Protein Kinase Inhibitors
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one