Miao, Benchun ; Skidan, Igor ; Yang, Jinsheng ; Lugovskoy, Alexey ; Reibarkh, Mikhail ; Long, Kai ; Brazell, Tres ; Durugkar, Kulbhushan A. ; Maki, Jenny ; Ramana, C. V. ; Schaffhausen, Brian ; Wagner, Gerhard ; Torchilin, Vladimir ; Yuan, Junying ; Degterev, Alexei (2010) Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains Proceedings of the National Academy of Sciences, 107 (46). pp. 20126-20131. ISSN 0027-8424
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Official URL: http://www.pnas.org/content/107/46/20126.full
Related URL: http://dx.doi.org/10.1073/pnas.1004522107
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 (IC50 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.
Item Type: | Article |
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Source: | Copyright of this article belongs to National Academy of Sciences. |
ID Code: | 106015 |
Deposited On: | 01 Feb 2018 16:54 |
Last Modified: | 01 Feb 2018 16:54 |
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