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

• Published in: Biochemical pharmacology 2009-12, Vol.78 (12), p.1438-1447
• Main Authors: Wood, Edgar R., Shewchuk, Lisa, Hassel, Anne, Nichols, Jim, Truesdale, Anne T., Smith, Danielle, Carter, H. Luke, Weaver, Kurt, Barrett, George, Leesnitzer, Tony, Alvarez, Emilio, Bardera, Ana Isabel, Alamillo, Amelia, Cantizani, Juan, Martin, Julio, Smith, Gary K., Jensen, David E., Xie, Hongbo, Mook, Robert, Kumar, Rakesh, Kuntz, Kevin
• Format: Article
• Language: English
• Subjects: Adipocytes - drug effects; Animals; Binding Sites; Biological and medical sciences; Cancer; Humans; Inhibitory Concentration 50; Insulin-like growth factor receptor; Kinase inhibitor; Medical sciences; Mice; NIH 3T3 Cells; Pharmacology. Drug treatments; Phosphorylation; Phosphotransferases - antagonists & inhibitors; Receptor tyrosine kinase; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, Insulin - drug effects; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.07.022

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.