Edgar R Wood,
Lisa Shewchuk,
Anne Hassel,
Jim Nichols,
Anne T Truesdale,
Danielle Smith,
H Luke Carter,
Kurt Weaver,
George Barrett,
Tony Leesnitzer, [......],
Ana Isabel Bardera,
Amelia Alamillo,
Juan Cantizani,
Julio Martin,
Gary K Smith, David E Jensen,
Hongbo Xie,
Robert Mook,
Rakesh Kumar,
Kevin Kuntz
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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.
Biochemical pharmacology 09/2009; 78(12):1438-47. · 4.25 Impact Factor
