AKT crystal structure and AKT-specific inhibitors

Kumar, Chandan; Madison, Vincent

doi:10.1038/sj.onc.1209087

Cited by 194 publications

(207 citation statements)

References 44 publications

(35 reference statements)

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“…The crystal structure of the Akt PH domain with I(1,3,4,5)P 4 bound44 , 45 shows strong interactions of the protein with the 3-and 4-phosphate groups (not the 5-phosphate which was poised towards solvent and not tightly held). Given the importance of the phosphate monoester interactions in this structure, it might be surprising that the 3-deoxy-PIs bind at all to the PH domain.…”

Section: Discussionmentioning

confidence: 99%

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

et al. 2008

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D-3-Deoxy-phosphatidylinositol derivatives have cytotoxic activity against various human cancer cell lines. These phosphatidylinositols have a potentially wide array of targets in the phosphatidylinositol-3-kinase (PI3K)/Akt signaling network. To explore the specificity of these types of molecules, we have synthesized D-3-deoxy-dioctanoylphosphatidylinositol (D-3-deoxydiC 8 PI), D-3,5-dideoxy-diC 8 PI and D-3-deoxy-dioctanoylphosphatidylinositol-5-phosphate and their enantiomers, characterized their aggregate formation by novel high resolution field cycling 31 P NMR, and examined their susceptibility to phospholipase C (PLC) and their effects on the catalytic activity of PI3K and PTEN against diC 8 PI and dioctanoylphosphatidylinositol-3-phosphate substrates, respectively, as well as their ability to induce the death of the U937 human leukemic monocyte lymphoma cells. Of these molecules, only D-3-deoxy-diC 8 PI was able to promote cell death; it did so with an IC 50 of 40 μM, well below the CMC of 0.4 mM. Under these conditions, there was little inhibition of PI3K or PTEN observed in assays of recombinant enzymes (although the complete series of deoxy-PI compounds did provide insights into ligand binding by PTEN). The D-3-deoxydiC 8 PI was a poor substrate and not an inhibitor of the PLC enzymes. The in vivo results are consistent with the current thought that the PI analogue acts on Akt1 since the transcription initiation factor eIF4e, which is a downstream signaling target of the PI3K/Akt pathway, exhibited reduced phosphorylation on Ser209. Phosphorylation of Akt1 on Ser473, but not Thr308, was reduced. Since the potent cytotoxicity for U937 cells is completely lost with the L-3-deoxy-diC 8 PI as well as with modification of the hydroxyl group at the inositol C5 (either replacing the -OH with a hydrogen or phosphorylating it) in D-3-deoxy-diC 8 PI, both chirality of the phosphoinositol moiety and the hydroxyl group at C5 are major determinants of 3-deoxy-PI binding to its target in cells.

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Section: Discussionmentioning

confidence: 99%

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

et al. 2008

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“…From the global output prospective, the output states 0000, 1000, and 2000 are prominently represented because those outputs were associated with 3,967 of the 10,000 random inputs. The outputs 1000 and 2000 represent quiescent states in which the outputs are inactive, with the exception of Akt, a protein that must remain active to suppress apoptosis (24). The state 0000 would be associated with apoptosis because Akt activity is very low.…”

Section: Resultsmentioning

confidence: 99%

Emergent decision-making in biological signal transduction networks

Helikar

Konvalina

Heidel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

184

224

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The complexity of biochemical intracellular signal transduction networks has led to speculation that the high degree of interconnectivity that exists in these networks transforms them into an information processing network. To test this hypothesis directly, a large scale model was created with the logical mechanism of each node described completely to allow simulation and dynamical analysis. Exposing the network to tens of thousands of random combinations of inputs and analyzing the combined dynamics of multiple outputs revealed a robust system capable of clustering widely varying input combinations into equivalence classes of biologically relevant cellular responses. This capability was nontrivial in that the network performed sharp, nonfuzzy classifications even in the face of added noise, a hallmark of real-world decision-making.information processing ͉ systems biology

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“…176 Indeed, the Akt isoform PH domains are only about 30% identical to PH domains in other proteins. 177 Importantly, PIAs selectively induced apoptosis in several cancer cell lines that have high levels of Akt phoshorylation and were only modestly active in tumor cells displaying low levels of phosphorylated Akt. 178 Moreover, one of these compounds, PX-316, displayed in vivo antitumor activity against human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice.…”

Section: Pdk-1 Inhibitorsmentioning

confidence: 99%