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Targeting phospshatidylinositol 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)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.
AuthorsBenchun Miao, Alexei Degterev
JournalAutophagy (Autophagy) Vol. 7 Issue 6 Pg. 650-1 (Jun 2011) ISSN: 1554-8635 [Electronic] United States
PMID21460619 (Publication Type: Journal Article)
Chemical References
  • Enzyme Inhibitors
  • Phosphatidylinositol Phosphates
  • Phosphoinositide-3 Kinase Inhibitors
  • phosphatidylinositol 3,4,5-triphosphate
Topics
  • Animals
  • Chemistry, Pharmaceutical (methods)
  • Drug Design
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Mice
  • Models, Biological
  • Mutation
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphatidylinositol Phosphates (antagonists & inhibitors, chemistry)
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction

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