Functional characterization of an isoform-selective inhibitor of PI3K-p110ß as a potential anticancer agent.

ABSTRACT

UNLABELLED Genetic approaches have shown that the p110ß isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110ß-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 p110ß inhibitor KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110ß 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 p110ß in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110ß while sparing other PI3K isoforms. SIGNIFICANCE: We report the first functional characterization of a p110ß-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 p110ß-dependent PTEN-deficient human tumors.