Discovery of an inhibitor of insulin-like growth factor 1 receptor activation: implications for cellular potency and selectivity over insulin receptor.
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.
Wood
Edgar R
ER
Department of Biological Reagents and Assay Development, Research Triangle Park, GlaxoSmithKline, Inc., NC 27709, United States. erw39216@gsk.com
Shewchuk
Lisa
L
Hassel
Anne
A
Nichols
Jim
J
Truesdale
Anne T
AT
Smith
Danielle
D
Carter
H Luke
HL
Weaver
Kurt
K
Barrett
George
G
Leesnitzer
Tony
T
Alvarez
Emilio
E
Bardera
Ana Isabel
AI
Alamillo
Amelia
A
Cantizani
Juan
J
Martin
Julio
J
Smith
Gary K
GK
Jensen
David E
DE
Xie
Hongbo
H
Mook
Robert
R
Kumar
Rakesh
R
Kuntz
Kevin
K
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
D010770:Phosphotransferases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin