Our present study has shown that the IGF-1R intracellular domain directly binds to the NT2 domain of FAK in vitro ( Fig. 2), and that the FAK-NT2 domain co-localizes with IGF-1R in pancreatic cancer
UK-383367 ( Fig. 3). Targeting this interaction with small molecules is a novel strategy for treatment of pancreatic cancer or other cancers. The binding assays conducted in the present study defines the interaction site as the FAK-NT2 domain and N-terminal part of the IGF-1R intracellular domain, allowing the use of a highly efficient computer program DOT to predict the binding model based on the resolved crystal structures of the FAK-NT domain and IGF-1R kinase domain. DOT was able to find stable docked structures for FAK-NT2 and IGF-1R kinase domain by performing a systematic search over six degrees of freedom, producing the most favorable binding models. Since DOT is restricted to rigid molecules, and does not take solvation
energy into account, the favorable points of interaction between FAK-NT2 and IGF-1 kinase may not be exact. But this approach does provide working models for screening of small molecules that effectively block the protein–protein interaction of interest, demonstrated by the successful identification of Compound 32 as a blocker of FAK/IGF-1R interaction ( Fig. 4D). Since the structure of the IGF-1R juxtamembrane domain is not available for DOT analysis, our present data could not rule out the binding of FAK-NT2 to this part of IGF-1R.
