A Novel Small-Molecule Inhibitor of Protein Kinase Cι Blocks Transformed Growth of Non–Small-Cell Lung Cancer Cells

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Abstract
We recently showed that atypical protein kinase Cι (PKCι) is required for transformed growth of human non–small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKCι signaling blocks Rac1 activity and transformed growth, indicating that PKCι is a viable target for development of novel therapeutics for NSCLC. Here, we designed and implemented a novel fluorescence resonance energy transfer–based assay to identify inhibitors of oncogenic PKCι signaling. This assay was used to identify compounds that disrupt the interaction between PKCι and its downstream effector Par6, which links PKCι to Rac1. We identified aurothioglucose (ATG), a gold compound used clinically to treat rheumatoid arthritis, and the related compound, aurothiomalate (ATM), as potent inhibitors of PKCι-Par6 interactions in vitro (IC50 ∼1 μmol/L). ATG blocks PKCι-dependent signaling to Rac1 and inhibits transformed growth of NSCLC cells. ATG-mediated inhibition of transformation is relieved by expression of constitutively active Rac1, consistent with a mechanism at the level of the interaction between PKCι and Par6. ATG inhibits A549 cell tumor growth in nude mice, showing efficacy against NSCLC in a relevant preclinical model. Our data show the utility of targeting protein-protein interactions involving PKCι for antitumor drug development and provide proof of concept that chemical disruption of PKCι signaling can be an effective treatment for NSCLC. ATG and ATM will be useful reagents for studying PKCι function in transformation and represent promising new agents for the clinical treatment of NSCLC. (Cancer Res 2006; 66(3): 1767-74)