title: Discovery of an inhibitor of insulin-like growth factor 1 receptor activation: implications for cellular potency and selectivity over insulin receptor.
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.
authors: Department of Biological Reagents and Assay Development, Research Triangle Park, GlaxoSmithKline, Inc., NC 27709, United States. erw39216@gsk.com
authors: Edgar R
authors: ER
authors: Wood
authors: Lisa
authors: L
authors: Shewchuk
authors: Anne
authors: A
authors: Hassel
authors: Jim
authors: J
authors: Nichols
authors: Anne T
authors: AT
authors: Truesdale
authors: Danielle
authors: D
authors: Smith
authors: H Luke
authors: HL
authors: Carter
authors: Kurt
authors: K
authors: Weaver
authors: George
authors: G
authors: Barrett
authors: Tony
authors: T
authors: Leesnitzer
authors: Emilio
authors: E
authors: Alvarez
authors: Ana Isabel
authors: AI
authors: Bardera
authors: Amelia
authors: A
authors: Alamillo
authors: Juan
authors: J
authors: Cantizani
authors: Julio
authors: J
authors: Martin
authors: Gary K
authors: GK
authors: Smith
authors: David E
authors: DE
authors: Jensen
authors: Hongbo
authors: H
authors: Xie
authors: Robert
authors: R
authors: Mook
authors: Rakesh
authors: R
authors: Kumar
authors: Kevin
authors: K
authors: Kuntz
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D010770:Phosphotransferases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin