Functional Characterization of an Isoform-Selective Inhibitor of PI3K-p110β as a Potential Anticancer Agent

Genetic approaches have shown that the p110 beta isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110 beta-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110 beta inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110 beta activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110 beta in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110 beta while sparing other PI3K isoforms. SIGNIFICANCE: We report the first functional characterization of a p110 beta-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110 beta-dependent PTEN-deficient human tumors. Cancer Discov; 2(5); 425-33. (c) 2012 AACR.