Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure

Bioorg Med Chem Lett. 2006 Dec 15;16(24):6281-7. doi: 10.1016/j.bmcl.2006.09.038. Epub 2006 Sep 26.


The extracellular signal-regulated kinases (ERK1 and ERK2) are important mediators of cell proliferation. Constitutive activation of the ERK proteins plays a critical role in the proliferation of many human cancers. Taking advantage of recently identified substrate docking domains on ERK2, we have used computer-aided drug design (CADD) to identify novel low molecular weight compounds that interact with ERK2 in an ATP-independent manner and disrupt substrate-specific interactions. In the current study, a CADD screen of the 3D structure of active phosphorylated ERK2 protein was used to identify inhibitory compounds. We tested 13 compounds identified by the CADD screen in ERK-specific phosphorylation, cell proliferation, and binding assays. Of the 13 compounds tested, 4 compounds strongly inhibited ERK-mediated phosphorylation of ribosomal S6 kinase-1 (Rsk-1) and/or the transcription factor Elk-1 and inhibited the proliferation of HeLa cervical carcinoma cells with IC(50) values in the 2-10 microM range. These studies demonstrate that CADD can be used to identify lead compounds for development of novel non-ATP-dependent inhibitors selective for active ERK and its interactions with substrates involved in cancer cell proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology*
  • Binding Sites
  • Kinetics
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / chemistry*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / chemistry*
  • Models, Molecular
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*


  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3