Small-molecule ATP-competitive dual IGF-1R and insulin receptor inhibitors: structural insights, chemical diversity and molecular evolution

Future Med Chem. 2012 Mar;4(3):315-28. doi: 10.4155/fmc.11.180.


IGF-1R has been recognized as a major target in cancer drug discovery due to its strong implications in various stages of tumorigenesis based on accumulated preclinical data. Recent research on compensatory crosstalk between IGF-1R and insulin receptor (IR) signaling pathways suggests that targeting both IGF-1R and IR should result in a more therapeutically beneficial response, than targeting IGF-1R alone (e.g., IGF-1R-specific antibodies). These findings provided biological rationale and opened the door to the discovery of a variety of small-molecule dual IGF-1R and IR inhibitors. In this review we summarize the recent developments in this field, with a focus on binding modes and binding interactions of these inhibitors with IGF-1R and/or IR. Selectivity of these inhibitors has been discussed in this context as well. This is an important area to be discussed since one of the major challenges in kinase inhibitor drug discovery is to build an optimal selectivity profile based on biological rationale.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / antagonists & inhibitors*
  • Receptor, Insulin / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Adenosine Triphosphate
  • Receptor, IGF Type 1
  • Receptor, Insulin