Abstract 1161 Discovery of Small-Molecule Inhibitor that Prolongs Class I PI3K Catalytic Activity via a Unique Regulatory Mechanism

The class I phosphoinositide 3-kinase (PI3K) produces phosphatidylinositol (3,4,5)-trisphosphate (PIP3) from phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) at the inner plasma membrane under cell stimulation. Since PI3K is one of the most mutated proteins in human cancers, it has been a prominent target for cancer drug development. While the mechanism of PI3K activation is well understood, the mechanism of its signaling termination remains elusive. In this study, we report a new mechanism by which PI3K activation is terminated by Class II PI3K- and PIKFyve-mediated generation of a rare lipid, phosphatidylinositol (3,5)-bisphosphate (PI(3,5)P2).