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)P 3).
PtdIns(3,4,5)P 3 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) P 3 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)P 3 antagonists, PIT-1 and PIT-2. Further cellular analysis revealed that both PITs inhibit
PtdIns(3,4,5) P 3-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)P 3 antagonists recently described by other laboratories suggest the possibility of targeting a key universal
PtdIns(3,4,5)P 3/PH domain binding step in the PtdIns3K pathway using heterologous small molecule modulators.