Influence of kinetics of drug binding on EGFR signaling: a comparative study of three EGFR signaling pathway models

Proteins. 2011 Aug;79(8):2491-504. doi: 10.1002/prot.23072. Epub 2011 Jun 2.

Abstract

We used three models of the epidermal growth factor receptor (EGFR) signaling pathway mimicking three different cell lines to study the effects of kinetics of drug binding on influencing molecular signaling in the pathways. With no incubation of drugs before the external cue epidermal growth factor (EGF) was applied, we found that fast kinetics of binding to protein kinases was advantageous in suppressing the production of the Extracellular signal-regulated kinase (ERK) that triggers cell proliferation, with some exceptions. Incubation of a drug with a protein kinase target for an hour before a pathway was initiated with an external cue made kinetics less significant, so did high concentration of drugs. In addition, we found that applying a drug to a protein kinase mostly affected downstream signaling although upstream events were also affected in a few cases. In examining whether applying two drugs to two protein kinase targets in the pathways could produce synergistic effects, we found positive, negative, or no effects, depending on the protein kinases targeted and the pathway model considered.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Computer Simulation*
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Kinetics
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism
  • Protein Binding
  • Signal Transduction / physiology

Substances

  • Pharmaceutical Preparations
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases