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J Biol Chem. 2013 Sep 27;288(39):28068-77. doi: 10.1074/jbc.M113.505032. Epub 2013 Aug 9.

A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor.

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From the Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.


Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.


ERK; Enzyme Inhibitors; High Throughput Screening (HTS); Insulin Receptor; Insulin-like Growth Factor 1 Receptor; Kinase Inhibitor; Receptor Tyrosine Kinase; Small-molecule Inhibition; X-ray Crystallography

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