↵2 Present address: Abramson Family Cancer Research Institute, Dept. of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 525 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104.

Background: IR/IGF-1R kinase inhibitors are promising therapeutic agents in cancer.

Results: Irfin1, a compound closely related to the ERK inhibitor FR180204, inhibits IR/IGF-1R family kinases.

Conclusion: Irfin1 is a remarkably selective inhibitor for the inactive states of IR/IGF-1R kinases.

Significance: Broad spectrum kinase inhibitor profiling can be exploited to uncover novel targets of small-molecule compounds.

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.

↵* This work was supported by the National Institutes of Health Grants GM083025 (to J. R. P.), T32 CA009035-36 (to K. C. D.), and P30 CA006927 (to the Fox Chase Cancer Center) and by a W. W. Smith Charitable Trust Award. This work was also supported by the FCCC Keystone Program in Head and Neck Cancer.

The atomic coordinates and structure factors (code 4IBM) have been deposited in the Protein Data Bank (http://wwpdb.org/).