Development of Novel Small Molecule Inhibitors of the Phosphoinositide-3-Kinase Pathway Through High-Throughput Cell-Based Screens

摘要

Our group previously showed that FOXO proteins are aberrantly localized to the cytoplasm in cells that have sustained loss of functional PTEN. Moreover, reconstitution of PTEN function to such cells leads to restoration of FOXO to the nucleus. To a first approximation, small molecules that recapitulate this activity of PTEN, i.e. lead to re-distribution of FKHR from the cytoplasm to the nucleus, should lead to inhibition of cell-cycle progression and suppression of tumorigenicity of PTEN null cells. These data led us to ask whether a novel cell-based small-molecule screen could be developed using FKHR localization as an end-point. preliminary data showed that this was feasible and led to the discovery of novel small molecule inhibitors of the PI3K pathway. Based on these results we proposed 3 specific aims: (1) To determine the mechanism of action of inhibitors that specifically re-localize FKHR to the nucleus (2) To determine the in vitro biological activity of small molecule inhibitors discovered in the FKHR screen. (3) To determine the in vivo anti-tumor efficacy of lead compounds in animal models.