Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex

Biochem Biophys Res Commun. 2005 Oct 14;336(1):357-63. doi: 10.1016/j.bbrc.2005.08.082.


Selective inhibition of extracellular signal-regulated kinase (ERK) represents a potential approach for the treatment of cancer and other diseases; however, no selective inhibitors are currently available. Here, we describe an ERK-selective inhibitor, FR180204, and determine the structural basis of its selectivity. FR180204 inhibited the kinase activity of ERK1 and ERK2, with K(i) values 0.31 and 0.14microM, respectively. Lineweaver-Burk analysis of the binding interaction revealed that FR180204 acted as competitive inhibitor of ATP. In mink lung epithelial Mv1Lu cells, FR180204 inhibited TGFbeta-induced luciferase-expression. X-ray crystal structure analysis of the human ERK2/FR180204 complex revealed that Q105, D106, L156, and C166, which form the ATP-binding pocket on ERK, play important roles in the drug/protein interaction. These results suggest that FR180204 is an ERK-selective and cell-permeable inhibitor, and could be useful for elucidating the roles of ERK as well as for drug development.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Mink
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / chemistry
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Sequence Homology, Amino Acid
  • Substrate Specificity


  • Enzyme Inhibitors
  • FR 180204
  • Pyrazoles
  • Pyridazines
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3