1. Academic Validation
  2. Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains

Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains

  • Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20126-31. doi: 10.1073/pnas.1004522107.
Benchun Miao 1 Igor Skidan Jinsheng Yang Alexey Lugovskoy Mikhail Reibarkh Kai Long Tres Brazell Kulbhushan A Durugkar Jenny Maki C V Ramana Brian Schaffhausen Gerhard Wagner Vladimir Torchilin Junying Yuan Alexei Degterev
Affiliations

Affiliation

  • 1 Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Abstract

The PI3-kinase (PI3K) pathway regulates many cellular processes, especially cell metabolism, cell survival, and Apoptosis. Phosphatidylinositol-3,4,5-trisphosphate (PIP3), the product of PI3K activity and a key signaling molecule, acts by recruiting pleckstrin-homology (PH) domain-containing proteins to cell membranes. Here, we describe a new structural class of nonphosphoinositide small molecule antagonists (PITenins, PITs) of PIP3-PH domain interactions (IC(50) ranges from 13.4 to 31 μM in PIP3/Akt PH domain binding assay). PITs inhibit interactions of a number of PIP3-binding PH domains, including those of Akt and PDK1, without affecting several PIP2-selective PH domains. As a result, PITs suppress the PI3K-PDK1-Akt pathway and trigger metabolic stress and Apoptosis. A PIT-1 analog displayed significant antitumor activity in vivo, including inhibition of tumor growth and induction of Apoptosis. Overall, our studies demonstrate the feasibility of developing specific small molecule antagonists of PIP3 signaling.

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Products
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    Description
    Target
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  • HY-103224
    98.56%, PI3K抑制剂