A novel small-molecule inhibitor of protein kinase Cι blocks transformed growth of non-small-cell lung cancer cells

We recently showed that atypical protein kinase C iota (PKC iota) is required for transformed growth of human non-small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKC iota signaling blocks Rac1 activity and transformed growth, indicating that PKC iota 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 PKC iota signaling. This assay was used to identify compounds that disrupt the interaction between PKC iota and its downstream effector Par6, which links PKC iota 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 PKC iota-Par6 interactions in vitro (IC50 - 1 mu mol/L). ATG blocks PKC iota-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 PKC iota 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 PKC iota for antitumor drug development and provide proof of concept that chemical disruption of PKC iota signaling can be an effective treatment for NSCLC. ATG and ATM will be useful reagents for studying PKC iota function in transformation and represent promising new agents for the clinical treatment of NSCLC.