Discovery of an inhibitor of insulin-like growth factor 1 receptor activation: implications for cellular potency and selectivity over insulin receptor

Biochem Pharmacol. 2009 Dec 15;78(12):1438-47. doi: 10.1016/j.bcp.2009.07.022. Epub 2009 Aug 7.

Abstract

Insulin-like growth factor 1 receptor (IGF-1R) is an attractive target for anti-cancer therapy due to its anti-apoptotic effect on tumor cells, but inhibition of insulin receptor (IR) may have undesired metabolic consequences. The primary sequences of the ATP substrate-binding sites of these receptors are identical and the crystal structures of the activated kinase domains are correspondingly similar. Thus, most small-molecule inhibitors described to date are equally potent against the activated kinase domains of IGF-1R and IR. In contrast, the non-phosphorylated kinase domains of these receptors have several structural features that may accommodate differences in binding affinity for kinase inhibitors. We used a cell-based assay measuring IGF-1R autophosphorylation as an inhibitor screen, and identified a potent purine derivative that is selective compared to IR. Surprisingly, the compound is a weak inhibitor of the activated IGF-1R tyrosine kinase domain. Biochemical and structural studies are presented that indicate the compound preferentially binds to the ATP site of non-phosphorylated IGF-1R compared to phosphorylated IGF-1R. The potential selectivity and potency advantages of this binding mode are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Animals
  • Binding Sites
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation
  • Phosphotransferases / antagonists & inhibitors
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, Insulin / drug effects*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship

Substances

  • Phosphotransferases
  • Receptor, IGF Type 1
  • Receptor, Insulin