Targeting phopshatidylinositol-3-kinase signaling with novel phosphatidylinositol 3,4,5-triphosphate antagonists

Abstract

The critical role of phopshatidylinositol- 3-kinase (PtdIns3K) signaling in the regulation of a wide range of cellular functions, including cell survival and proliferation, autophagy, metabolism and cell migration, is well recognized. Activation of PtdIns3K leads to the generation of phosphatidylinositol- 3,4,5-triphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 activates a complex signaling network controlling these diverse cellular functions through binding to Pleckstrin Homology (PH) domains of the effector proteins. We have recently described a new structural class of nonphosphoinositide small molecule inhibitors targeting binding of PtdIns(3,4,5) P3 to PH domain targets. Using an in vitro PtdIns(3,4,5)P 3-PH domain binding assay, we identified two distinct PtdIns(3,4,5)P3 antagonists, PIT-1 and PIT-2. Further cellular analysis revealed that both PITs inhibit PtdIns(3,4,5) P3-dependent signaling mediated by Akt kinase, leading to the induction of apoptosis, metabolic stress and autophagy. An improved PIT-1 analog, DM-PIT-1, displays significant anticancer activity in the mouse syngeneic 4T1 breast cancer model in vivo. Discovery of PITs as well as other PtdIns(3,4,5)P3 antagonists recently described by other laboratories suggest the possibility of targeting a key universal PtdIns(3,4,5)P3/PH domain binding step in the PtdIns3K pathway using heterologous small molecule modulators. © 2011 Landes Bioscience.